The Association Between High-Sensitivity Cardiac Troponin T and Major Adverse Cardiovascular Events in Rheumatoid Arthritis.

Patients with rheumatoid arthritis (RA) have a 1.5-times excess risk of cardiovascular (CV) disease compared to the general population, attributed to chronic inflammation.1,2 In the general population, detectable levels of high-sensitivity cardiac troponin (hs-cTn) are associated with higher risk of major adverse CV events (MACE) and all-cause mortality.3.

Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis.

CD4+ T cells are central mediators of autoimmune pathology; however, defining their key effector functions in specific autoimmune diseases remains challenging. Pathogenic CD4+ T cells within affected tissues may be identified by expression of markers of recent activation. Here we use mass cytometry to analyse activated T cells in joint tissue from patients with rheumatoid arthritis, a chronic immune-mediated arthritis that affects up to 1% of the population. This approach revealed a markedly expanded population of PD-1hiCXCR5-CD4+ T cells in synovium of patients with rheumatoid arthritis. However, these cells are not exhausted, despite high PD-1 expression. Rather, using multidimensional cytometry, transcriptomics, and functional assays, we define a population of PD-1hiCXCR5- 'peripheral helper' T (TPH) cells that express factors enabling B-cell help, including IL-21, CXCL13, ICOS, and MAF. Like PD-1hiCXCR5+ T follicular helper cells, TPH cells induce plasma cell differentiation in vitro through IL-21 secretion and SLAMF5 interaction (refs 3, 4). However, global transcriptomics highlight differences between TPH cells and T follicular helper cells, including altered expression of BCL6 and BLIMP1 and unique expression of chemokine receptors that direct migration to inflamed sites, such as CCR2, CX3CR1, and CCR5, in TPH cells. TPH cells appear to be uniquely poised to promote B-cell responses and antibody production within pathologically inflamed non-lymphoid tissues.

Ambulatory Medication Reconciliation: Using a Collaborative Approach to Process Improvement at an Academic Medical Center.

BACKGROUND: Incomplete medication reconciliation has been identified as a source of adverse drug events and a threat to patient safety. How best to measure and improve rates of medication reconciliation in ambulatory care remains unknown. METHODS: An institutional collaborative improvement effort to develop and implement medication reconciliation processes was designed and facilitated across all 148 Brigham and Women's Hospital (Boston) ambulatory specialty practices: 63 underwent a more rigorous approach, a modified approach was undertaken in another 71 specialty practices, and a less intensive approach took place in the 14 primary care practices. The level of intervention varied on the basis of preexisting improvement infrastructure and practice prescription rates. Two electronically measured metrics were created to evaluate ambulatory visits to a provider in which there was a medication change: (1) Measure 1: the percentage of active medications prescribed by that provider that were reconciled; and (2) Measure 2: how often all the medications prescribed by that provider were reconciled. After the collaborative was completed, performance data were routinely shared with frontline staff and hospital leadership, and medication reconciliation rates became part of an institutional financial incentive program. RESULTS: For Measure 1, specialty practices improved from 71% to 90% (September 2012-August 2014; 24-month period). Primary care practice performance improved from 62% to 91% (December 2012-August 2014; 20-month period). For Measure 2, overall performance across all ambulatory practices increased from 81% to 90% during the first 12 months of the financial incentive program (October 2013- September 2014). CONCLUSION: A collaborative model of process improvement paired with financial incentives can successfully increase rates of ambulatory medication reconciliation.

Increasing pneumococcal vaccination for immunosuppressed patients: a cluster quality improvement trial.

OBJECTIVE: Pneumococcal vaccination is important for patients taking immunosuppressive medications, but prior studies suggest that most patients do not undergo vaccination. The aim of this study was to evaluate the effects of a point-of-care paper reminder form as a quality improvement (QI) strategy to increase the numbers of immunosuppressed patients being kept up-to-date with pneumococcal vaccination in a rheumatology practice. METHODS: Selected rheumatologists at 5 ambulatory practice sites received a point-of-care paper reminder form to be applied to patients who were not up-to-date with pneumococcal vaccination. Interrupted time-series analyses were used to measure the effect of the intervention on the pneumococcal vaccination rates among patients, comparing the rates in the intervention group with those in a control group of rheumatologists who did not receive the intervention. Adjusted Cox proportional hazards models were examined to identify independent predictors of being up-to-date with pneumococcal vaccination. RESULTS: We evaluated a total of 3,717 patients (66.0% with rheumatoid arthritis) who were taking immunosuppressive medications (74.1% women, mean age 53.7 years). Rheumatologists who received the intervention had a significant increase in the rate of patients who were up-to-date with pneumococcal vaccination, from 67.6% to 80.0% (P=0.006), in the time period following the intervention, compared to a rate that remained stable, from 52.3% to 52.0% (P=0.90), among patients in the nonintervention control group during this same time period. In regression models, positive predictors of being up-to-date with pneumococcal vaccination at the patient level included the following: having received the intervention (hazard ratio [HR] 3.58, 95% confidence interval [95% CI] 2.46-5.20), having a primary care physician affiliated with Brigham and Women's Hospital (HR 1.68, 95% CI 1.44-1.97), having a diagnosis of diabetes mellitus (HR 1.57, 95% CI 1.02-2.41), and being age 56-65 years at baseline, compared to age≤45 years (HR 1.24, 95% CI 1.01-1.51). CONCLUSION: A QI strategy involving a simple point-of-care paper reminder form significantly increased the rate of being up-to-date with pneumococcal vaccination among patients receiving immunosuppressive medications in our rheumatology practices over a 6-month period.

Reasons for multiple biologic and targeted synthetic DMARD switching and characteristics of treatment refractory rheumatoid arthritis.

OBJECTIVE: Switching biologic and targeted synthetic DMARD (b/tsDMARD) medications occurs commonly in RA patients, however data are limited on the reasons for these changes. The objective of the study was to identify and categorize reasons for b/tsDMARD switching and investigate characteristics associated with treatment refractory RA. METHODS: In a multi-hospital RA electronic health record (EHR) cohort, we identified RA patients prescribed ≥1 b/tsDMARD between 2001 and 2017. Consistent with the EULAR "difficult to treat" (D2T) RA definition, we further identified patients who discontinued ≥2 b/tsDMARDs with different mechanisms of action. We performed manual chart review to determine reasons for medication discontinuation. We defined "treatment refractory" RA as not achieving low disease activity (<3 tender or swollen joints on <7.5 mg of daily prednisone equivalent) despite treatment with two different b/tsDMARD mechanisms of action. We compared demographic, lifestyle, and clinical factors between treatment refractory RA and b/tsDMARD initiators not meeting D2T criteria. RESULTS: We identified 6040 RA patients prescribed ≥1 b/tsDMARD including 404 meeting D2T criteria. The most common reasons for medication discontinuation were inadequate response (43.3 %), loss of efficacy (25.8 %), and non-allergic adverse events (13.7 %). Of patients with D2T RA, 15 % had treatment refractory RA. Treatment refractory RA patients were younger at b/tsDMARD initiation (mean 47.2 vs. 55.2 years, p < 0.001), more commonly female (91.8% vs. 76.1 %, p = 0.006), and ever smokers (68.9% vs. 49.9 %, p = 0.005). No RA clinical factors differentiated treatment refractory RA patients from b/tsDMARD initiators. CONCLUSIONS: In a large EHR-based RA cohort, the most common reasons for b/tsDMARD switching were inadequate response, loss of efficacy, and nonallergic adverse events (e.g. infections, leukopenia, psoriasis). Clinical RA factors were insufficient for differentiating b/tsDMARD responders from nonresponders.

Interplay Between Systemic Inflammation, Myocardial Injury, and Coronary Microvascular Dysfunction in Rheumatoid Arthritis: Results From the LiiRA Study.

BACKGROUND: Coronary microvascular dysfunction as measured by myocardial flow reserve (MFR) is associated with increased cardiovascular risk in rheumatoid arthritis (RA). The objective of this study was to determine the association between reducing inflammation with MFR and other measures of cardiovascular risk. METHODS AND RESULTS: Patients with RA with active disease about to initiate a tumor necrosis factor inhibitor were enrolled (NCT02714881). All subjects underwent a cardiac perfusion positron emission tomography scan to quantify MFR at baseline before tumor necrosis factor inhibitor initiation, and after tumor necrosis factor inhibitor initiation at 24 weeks. MFR <2.5 in the absence of obstructive coronary artery disease was defined as coronary microvascular dysfunction. Blood samples at baseline and 24 weeks were measured for inflammatory markers (eg, high-sensitivity C-reactive protein [hsCRP], interleukin-1b, and high-sensitivity cardiac troponin T [hs-cTnT]). The primary outcome was mean MFR before and after tumor necrosis factor inhibitor initiation, with Δhs-cTnT as the secondary outcome. Secondary and exploratory analyses included the correlation between ΔhsCRP and other inflammatory markers with MFR and hs-cTnT. We studied 66 subjects, 82% of which were women, mean RA duration 7.4 years. The median atherosclerotic cardiovascular disease risk was 2.5%; 47% had coronary microvascular dysfunction and 23% had detectable hs-cTnT. We observed no change in mean MFR before (2.65) and after treatment (2.64, P=0.6) or hs-cTnT. A correlation was observed between a reduction in hsCRP and interleukin-1b with a reduction in hs-cTnT. CONCLUSIONS: In this RA cohort with low prevalence of cardiovascular risk factors, nearly 50% of subjects had coronary microvascular dysfunction at baseline. A reduction in inflammation was not associated with improved MFR. However, a modest reduction in interleukin-1b and no other inflammatory pathways was correlated with a reduction in subclinical myocardial injury. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02714881.

Utilizing biologic disease-modifying anti-rheumatic treatment sequences to subphenotype rheumatoid arthritis.

BACKGROUND: Many patients with rheumatoid arthritis (RA) require a trial of multiple biologic disease-modifying anti-rheumatic drugs (bDMARDs) to control their disease. With the availability of several bDMARD options, the history of bDMARDs may provide an alternative approach to understanding subphenotypes of RA. The objective of this study was to determine whether there exist distinct clusters of RA patients based on bDMARD prescription history to subphenotype RA. METHODS: We studied patients from a validated electronic health record-based RA cohort with data from January 1, 2008, through July 31, 2019; all subjects prescribed ≥ 1 bDMARD or targeted synthetic (ts) DMARD were included. To determine whether subjects had similar b/tsDMARD sequences, the sequences were considered as a Markov chain over the state-space of 5 classes of b/tsDMARDs. The maximum likelihood estimator (MLE)-based approach was used to estimate the Markov chain parameters to determine the clusters. The EHR data of study subjects were further linked with a registry containing prospectively collected data for RA disease activity, i.e., clinical disease activity index (CDAI). As a proof of concept, we tested whether the clusters derived from b/tsDMARD sequences correlated with clinical measures, specifically differing trajectories of CDAI. RESULTS: We studied 2172 RA subjects, mean age 52 years, RA duration 3.4 years, and 62% seropositive. We observed 550 unique b/tsDMARD sequences and identified 4 main clusters: (1) TNFi persisters (65.7%), (2) TNFi and abatacept therapy (8.0%), (3) on rituximab or multiple b/tsDMARDs (12.7%), (4) prescribed multiple therapies with tocilizumab predominant (13.6%). Compared to the other groups, TNFi persisters had the most favorable trajectory of CDAI over time. CONCLUSION: We observed that RA subjects can be clustered based on the sequence of b/tsDMARD prescriptions over time and that the clusters were correlated with differing trajectories of disease activity over time. This study highlights an alternative approach to consider subphenotyping of patients with RA for studies aimed at understanding treatment response.

Pregnancy Intention Screening in Patients With Systemic Rheumatic Diseases: Pilot Testing a Standardized Assessment Tool.

OBJECTIVE: Systemic rheumatic conditions affect reproductive-aged patients and often require potentially teratogenic medications. We assessed the feasibility and impact of a standardized pregnancy intention screening question (One Key Question [OKQ]) in a large academic rheumatology practice. METHODS: This 6-month pilot quality improvement initiative prompted rheumatologists to ask female patients aged 18 to 49 years about their pregnancy intentions using OKQ. We administered surveys to assess rheumatologists' barriers to and comfort with reproductive health issues. We performed chart reviews to assess uptake and impact on documentation, comparing charts with OKQ documented with 100 randomly selected charts eligible for pregnancy intention screening but without OKQ documented. RESULTS: When we compared 32 of 43 preimplementation responses with 29 of 41 postimplementation responses, the proportion of rheumatologists who reported they were very comfortable with assessing their patients' reproductive goals increased (31%-38%) and the proportion reporting obstetrics and gynecology (OB/GYN) referral challenges as barriers to discussing reproductive goals decreased (41%-21%). During the implementation period, 83 of 957 (9%) eligible patients had OKQ documented in their chart. Female providers were more likely to screen than male providers (odds ratio 2.42, 95% confidence interval 1.21-4.85). Screened patients were more likely to have their contraceptive method documented (P < 0.001) and more likely to have been referred to OB/GYN for follow-up (P = 0.003) compared with patients who were not screened with OKQ. CONCLUSION: Although uptake was low, this tool improved provider comfort with assessing reproductive goals, the quality of documentation, and the likelihood of OB/GYN referral. Future studies should examine whether automated medical record alerts to prompt screening increase uptake.

Granzyme K+ CD8 T cells form a core population in inflamed human tissue.

T cell-derived pro-inflammatory cytokines are a major driver of rheumatoid arthritis (RA) pathogenesis. Although these cytokines have traditionally been attributed to CD4 T cells, we have found that CD8 T cells are notably abundant in synovium and make more interferon (IFN)-γ and nearly as much tumor necrosis factor (TNF) as their CD4 T cell counterparts. Furthermore, using unbiased high-dimensional single-cell RNA-seq and flow cytometric data, we found that the vast majority of synovial tissue and synovial fluid CD8 T cells belong to an effector CD8 T cell population characterized by high expression of granzyme K (GzmK) and low expression of granzyme B (GzmB) and perforin. Functional experiments demonstrate that these GzmK+ GzmB+ CD8 T cells are major cytokine producers with low cytotoxic potential. Using T cell receptor repertoire data, we found that CD8 GzmK+ GzmB+ T cells are clonally expanded in synovial tissues and maintain their granzyme expression and overall cell state in blood, suggesting that they are enriched in tissue but also circulate. Using GzmK and GzmB signatures, we found that GzmK-expressing CD8 T cells were also the major CD8 T cell population in the gut, kidney, and coronavirus disease 2019 (COVID-19) bronchoalveolar lavage fluid, suggesting that they form a core population of tissue-associated T cells across diseases and human tissues. We term this population tissue-enriched expressing GzmK or TteK CD8 cells. Armed to produce cytokines in response to both antigen-dependent and antigen-independent stimuli, CD8 TteK cells have the potential to drive inflammation.

SLAMF7 engagement superactivates macrophages in acute and chronic inflammation.

Macrophages regulate protective immune responses to infectious microbes, but aberrant macrophage activation frequently drives pathological inflammation. To identify regulators of vigorous macrophage activation, we analyzed RNA-seq data from synovial macrophages and identified SLAMF7 as a receptor associated with a superactivated macrophage state in rheumatoid arthritis. We implicated IFN-γ as a key regulator of SLAMF7 expression and engaging SLAMF7 drove a strong wave of inflammatory cytokine expression. Induction of TNF-α after SLAMF7 engagement amplified inflammation through an autocrine signaling loop. We observed SLAMF7-induced gene programs not only in macrophages from rheumatoid arthritis patients but also in gut macrophages from patients with active Crohn's disease and in lung macrophages from patients with severe COVID-19. This suggests a central role for SLAMF7 in macrophage superactivation with broad implications in human disease pathology.

Routinely measuring and reporting pneumococcal vaccination among immunosuppressed rheumatology outpatients: the first step in improving quality.

OBJECTIVE: The Centers for Disease Control (CDC) recommends pneumococcal vaccination for immunocompromised patients. Data suggest that rates of vaccination in this population are not optimal. To support continuous quality improvement efforts, we electronically measured vaccination status among rheumatology outpatients over time. METHODS: Using data from administrative (billing) and electronic health record sources, we identified rheumatology clinic patients seen between 1 February 2008 and 31 January 2010 and prescribed an immunosuppressive medication. CDC recommendations for pneumococcal vaccination were applied. We calculated the proportion of eligible patients who were up-to-date with pneumococcal vaccination: (i) while on an immunosuppressive medication and (ii) before newly starting an immunosuppressive medication in the last 12 months. RESULTS: We identified 2763 rheumatology clinic patients on immunosuppressive medications, with 568 initiated in the last 12 months. The mean age was 57 years, 75% were female and 77% were Caucasian. The most frequent disease was RA (50%) and the most common immunosuppressive medication was MTX (59%). Of patients on immunosuppressive medications, 1491/2763 (54%) were up to date with pneumococcal vaccination. Among new initiators of immunosuppressive medications, 258/568 (45%) were vaccinated before starting the immunosuppressive medication. Patients treated by rheumatologists in practice for ≤10 years were more likely to be up to date with pneumococcal vaccination (72%) than those with providers in practice >10 years (52%, P < 0.001). CONCLUSION: The proportion of patients who are up to date with documented pneumococcal vaccination was suboptimal in our rheumatology practice. The ability to continuously repeat electronic measurement permits us to initiate continuous quality improvement efforts.

Clinical predictors of erosion-free status in rheumatoid arthritis: a prospective cohort study.

OBJECTIVE: Treatment algorithms in RA include factors associated with poor prognosis; however, many patients remain erosion free despite years of disease. Our objective was to characterize the group of RA patients without erosions and identify its clinical predictors. METHODS: Our study was conducted within a prospective observational cohort of RA patients recruited from the outpatient practice of an academic medical centre. We studied patients with bilateral hand radiographs at cohort baseline and 2-year follow-up assessed with Sharp/van der Heijde scores (SHS). The primary outcome was erosion-free status at baseline and 2-year follow-up. We assessed baseline values of the following as potential correlates: age at RA onset, gender, RA duration, BMI, 28-joint DAS (DAS-28), CRP, anti-CCP status, tender and swollen joint counts, functional status [multidimensional HAQ (MDHAQ)], tobacco use and RA treatments. Variables with P ≤ 0.25 in the univariate analyses were assessed using backward selection in multivariable logistic regression models. RESULTS: Of the 271 subjects included, 21% (n = 56) were considered erosion free. Forty-six per cent (n = 26) of this group was anti-CCP positive compared with 56% (n = 121) in subjects with erosions present. Mean RA duration for erosion-free subjects was 3.9 years compared with 4.6 years in erosive subjects. Treatments for RA did not differ between the two groups. In the multivariable-adjusted analysis, significant predictors of erosion-free status were younger age at onset and shorter RA duration. CONCLUSION: In our cohort, 21% of subjects were erosion free at baseline and 2 years. Few baseline clinical characteristics significantly predicted erosion-free status.

Divergence of Cardiovascular Biomarkers of Lipids and Subclinical Myocardial Injury Among Rheumatoid Arthritis Patients With Increased Inflammation.

OBJECTIVE: Patients with rheumatoid arthritis (RA) are 1.5 times more likely to develop cardiovascular disease (CVD) attributed to chronic inflammation. A decrease in inflammation in patients with RA is associated with increased low-density lipoprotein (LDL) cholesterol. This study was undertaken to prospectively evaluate the changes in lipid levels among RA patients experiencing changes in inflammation and determine the association with concomitant temporal patterns in markers of myocardial injury. METHODS: A total of 196 patients were evaluated in a longitudinal RA cohort, with blood samples and high-sensitivity C-reactive protein (hsCRP) levels measured annually. Patients were stratified based on whether they experienced either a significant increase in inflammation (an increase in hsCRP of ≥10 mg/liter between any 2 time points 1 year apart; designated the increased inflammation cohort [n = 103]) or decrease in inflammation (a decrease in hsCRP of ≥10 mg/liter between any 2 time points 1 year apart; designated the decreased inflammation cohort [n = 93]). Routine and advanced lipids, markers of inflammation (interleukin-6, hsCRP, soluble tumor necrosis factor receptor II), and markers of subclinical myocardial injury (high-sensitivity cardiac troponin T [hs-cTnT], N-terminal pro-brain natriuretic peptide) were measured. RESULTS: Among the patients in the increased inflammation cohort, the mean age was 59 years, 81% were women, and the mean RA disease duration was 17.9 years. The average increase in hsCRP levels was 36 mg/liter, and this increase was associated with significant reductions in LDL cholesterol, triglycerides, total cholesterol, apolipoprotein (Apo B), and Apo A-I levels. In the increased inflammation cohort at baseline, 45.6% of patients (47 of 103) had detectable circulating hs-cTnT, which further increased during inflammation (P = 0.02). In the decreased inflammation cohort, hs-cTnT levels remained stable despite a reduction in inflammation over follow-up. In both cohorts, hs-cTnT levels were associated with the overall estimated risk of CVD. CONCLUSION: Among RA patients who experienced an increase in inflammation, a significant decrease in routinely measured lipids, including LDL cholesterol, and an increase in markers of subclinical myocardial injury were observed. These findings highlight the divergence in biomarkers of CVD risk and suggest a role in future studies examining the benefit of including hs-cTnT for CVD risk stratification in RA.

The Impact of Exercise, Lifestyle, and Clinical Factors on Perceived Cognitive Function in Patients with Rheumatoid Arthritis: Results from a Prospective Cohort Study.

OBJECTIVE: Lifestyle factors, such as inactivity and obesity, contribute to cognitive decline in the general population, but little is known about how these factors may affect individuals with a chronic inflammatory condition such as rheumatoid arthritis (RA). We studied the clinical and functional risk factors related to a worsening of perceived cognitive function in patients with RA. METHODS: We collected clinical and functional questionnaire data over 10 years in a prospective RA cohort including yearly self-reported memory, concentration, and word-finding difficulties graded from "never" to "often." Generalized estimating equation models examined the role of exercise (defined as those meeting the Department of Health and Human Services physical activity guidelines of 75 minutes of vigorous or 150 minutes of moderate aerobic activity per week), body mass index (BMI), sleep, depression (Mental Health Index-Depression), Disease Activity Score (DAS)28-c-reactive protein (CRP)3 score, disease-modifying antirheumatic drug, and corticosteroid use from the previous year as predictors of cognitive complaints that progressed to "often" compared with the previous year (the first year (T i ) progressed to "often" 1 year later (T i+1)). RESULTS: Of 1219 RA subjects, 127 (10.4%) described either poor memory, concentration, or word-finding difficulties as affecting them "often" at study entry. RA patients (n = 1092, mean age = 56.5 years, 82% female, 58% college educated) were less likely to report word-finding difficulties, poor memory, and concentration as "often" if they were physically active (p = 0.0001, P = 0.01, P < 0.0001, respectively). Female RA patients developed more concentration complaints compared with males (P = 0.03); patients taking an anti-tumor necrosis factor therapy were less likely to complain of poor memory (P = 0.01). Sleep, BMI, fatigue, depression, DAS28-CRP3, methotrexate, and corticosteroid use were not independently associated with a worsening of any cognitive complaints. CONCLUSION: RA patients who are physically active are less likely to report cognitive difficulties. Our study suggests potential modifiable risk factors for the prevention of cognitive dysfunction in RA.

Musculoskeletal and pulmonary outcomes of sarcoidosis after initial presentation of osseous involvement.

OBJECTIVE: We aimed to investigate the musculoskeletal and pulmonary outcomes of patients with osseous sarcoidosis. METHODS: We identified 24 patients with osseous sarcoidosis and at least one year of follow-up after diagnosis (baseline). We collected outcome data at 1-year follow-up and last follow-up. We defined a composite outcome measure; worsening considered as worsening in any of the following 4 components compared to baseline: 1) osseous sarcoidosis symptoms, 2) musculoskeletal imaging of affected bone, 3) chest imaging, or 4) pulmonary function testing (PFT). RESULTS: A minority of patients had a worsening composite outcome at 1-year (9/24, 38%) and last follow-up (5/24, 21%). When only considering musculoskeletal symptoms and imaging, only 25% (6/24) and 13% (3/24) of patients worsened compared to baseline at 1-year and last follow-up, respectively. Patients with a worsening composite overall outcome tended to be older at baseline than those without the outcome for both 1-year (54.3 years vs. 47.5 years, p=0.11) and last follow-up (55.0 years vs. 48.7 years; p=0.23), although these differences were non-significant. Treatment was not associated with worsening composite overall outcome at 1-year follow-up (p=0.40), but was significantly associated with decreased risk for worsening at last follow-up (p=0.05). CONCLUSIONS: In this retrospective cohort study of osseous sarcoidosis, most patients had a favorable outcome according to symptoms, musculoskeletal/chest imaging, and PFTs, even though only a minority were treated with glucocorticoids or DMARDs. These results suggest that the natural history of osseous sarcoidosis is often benign, although some patients experience clinical progression.

Progressive arm and leg stiffness in a patient with chronic renal impairment.

BACKGROUND: A 60-year-old white woman with a history of breast cancer, autoimmune hemolytic anemia, type 2 diabetes mellitus, peripheral vascular disease, and chronic renal insufficiency presented with stiffness in her arms and legs of 3 months' duration. She had undergone multiple MRI and magnetic resonance angiography examinations with gadolinium-containing contrast media over the last 2 years. INVESTIGATIONS: Complete physical examination including thorough skin examination; laboratory examinations including CBC, urinalysis, serum creatinine, protein electrophoresis and C-reactive protein; antinuclear antibody assay; Westergren erythrocyte sedimentation rate; and an excisional skin biopsy. DIAGNOSIS: Nephrogenic systemic fibrosis (also known as nephrogenic fibrosing dermopathy). MANAGEMENT: Symptomatic treatment, physical therapy, and a brief trial of imatinib mesylate.

Impact of Changes in Inflammation on Estimated Ten-Year Cardiovascular Risk in Rheumatoid Arthritis.

OBJECTIVE: Current validated cardiovascular (CV) risk estimates were developed in populations with relatively stable levels of inflammation, whereas patients with rheumatoid arthritis (RA) routinely experience significant changes in inflammation. This study was undertaken to test whether changes in inflammation affect estimated CV risk as measured using validated population-based risk calculators. METHODS: Participants in a prospective RA cohort who experienced a decrease or an increase of ≥10 mg/liter in the C-reactive protein (CRP) level at 2 consecutive time points 1 year apart (CRP decrease group and CRP increase group, respectively) were included in this study. We estimated 10-year CV risk using the following calculators: Framingham Risk Score, 2013 American College of Cardiology/American Heart Association Atherosclerotic Cardiovascular Disease Risk Score, Reynolds Risk Score (RRS), and QRISK2. Of these calculators, only the RRS includes a variable addressing the CRP level. Paired t-tests were performed to compare risk scores at baseline and 1-year follow-up. We calculated the correlations between the changes in risk scores and changes in pro-B-type natriuretic peptide (pro BNP), a surrogate marker of CV risk. RESULTS: One hundred eighty RA patients were included in the study (mean age 57.8 years, 84% female, 80% seropositive). Of the calculators studied, only the RRS was sensitive to changes in inflammation; an increase in inflammation was associated with increased estimated CV risk (P < 0.0001), and only the RRS was correlated with changes in proBNP (r = 0.17, P = 0.03). CONCLUSION: Our data showed no significant change in CV risk estimated using validated general population CV risk calculators except for the RRS. These findings suggest that CV risk may be modulated by changes in inflammation in RA, which is not typically considered when using existing CV risk calculators.

Mixed-effects association of single cells identifies an expanded effector CD4+ T cell subset in rheumatoid arthritis.

High-dimensional single-cell analyses have improved the ability to resolve complex mixtures of cells from human disease samples; however, identifying disease-associated cell types or cell states in patient samples remains challenging because of technical and interindividual variation. Here, we present mixed-effects modeling of associations of single cells (MASC), a reverse single-cell association strategy for testing whether case-control status influences the membership of single cells in any of multiple cellular subsets while accounting for technical confounders and biological variation. Applying MASC to mass cytometry analyses of CD4+ T cells from the blood of rheumatoid arthritis (RA) patients and controls revealed a significantly expanded population of CD4+ T cells, identified as CD27- HLA-DR+ effector memory cells, in RA patients (odds ratio, 1.7; P = 1.1 × 10-3). The frequency of CD27- HLA-DR+ cells was similarly elevated in blood samples from a second RA patient cohort, and CD27- HLA-DR+ cell frequency decreased in RA patients who responded to immunosuppressive therapy. Mass cytometry and flow cytometry analyses indicated that CD27- HLA-DR+ cells were associated with RA (meta-analysis P = 2.3 × 10-4). Compared to peripheral blood, synovial fluid and synovial tissue samples from RA patients contained about fivefold higher frequencies of CD27- HLA-DR+ cells, which comprised ~10% of synovial CD4+ T cells. CD27- HLA-DR+ cells expressed a distinctive effector memory transcriptomic program with T helper 1 (TH1)- and cytotoxicity-associated features and produced abundant interferon-γ (IFN-γ) and granzyme A protein upon stimulation. We propose that MASC is a broadly applicable method to identify disease-associated cell populations in high-dimensional single-cell data.

Fibromyalgia and the Prediction of Two-Year Changes in Functional Status in Rheumatoid Arthritis Patients.

OBJECTIVE: Previous cross-sectional studies have shown that rheumatoid arthritis (RA) patients with fibromyalgia (FM) have higher disease activity, greater medical costs, and worse quality of life compared to RA patients without FM. We determined the impact of FM on 2-year changes in the functional status of RA patients in a prospective study. METHODS: Subjects included participants in the Brigham Rheumatoid Arthritis Sequential Study who were enrolled in a substudy of the effects of pain in RA. Subjects completed questionnaires, including the Multi-Dimensional Health Assessment Questionnaire (MDHAQ) and Polysymptomatic Distress (PSD) scale, semiannually, and underwent physical examination and laboratory tests yearly. RESULTS: Of the 156 included RA subjects, 16.7% had FM, while 83.3% did not. In a multivariable linear regression model adjusted for age, sex, race, baseline MDHAQ score, disease duration, rheumatoid factor/cyclic citrullinated peptide antibody seropositivity, disease activity, and psychological distress, RA patients with FM had a 0.14 greater 2-year increase in MDHAQ score than RA patients without FM (P = 0.021). In secondary analyses examining the association between continuous PSD scale score and change in MDHAQ, higher PSD scale scores were significantly associated with greater 2-year increases in MDHAQ score (ß coefficient 0.013, P = 0.011). CONCLUSION: Both the presence of FM and increasing number of FM symptoms predicted worsening of functional status among individuals with RA. Among individuals with RA and FM, the magnitude of the difference in changes in MDHAQ was 4- to 7-fold higher than typical changes in MDHAQ score among individuals with established RA.