Publications by authors named "Nancy Shadick"

136 Publications

Geometric Features Associated with Middle Cerebral Artery Bifurcation Aneurysm Formation: A Matched Case-Control Study.

J Stroke Cerebrovasc Dis 2021 Dec 30;31(3):106268. Epub 2021 Dec 30.

Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA; Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA. Electronic address:

Objectives: The pathogenesis of intracranial aneurysms is multifactorial and includes genetic, environmental, and anatomic influences. We aimed to identify image-based morphological parameters that were associated with middle cerebral artery (MCA) bifurcation aneurysms.

Materials And Methods: We evaluated three-dimensional morphological parameters obtained from CT angiography (CTA) or digital subtraction angiography (DSA) from 317 patients with unilateral MCA bifurcation aneurysms diagnosed at the Brigham and Women's Hospital and Massachusetts General Hospital between 1990 and 2016. We chose the contralateral unaffected MCA bifurcation as the control group, in order to control for genetic and environmental risk factors. Diameters and angles of surrounding parent and daughter vessels of 634 MCAs were examined.

Results: Univariable and multivariable statistical analyses were performed to determine statistical significance. Sensitivity analyses with smaller (≤ 3 mm) aneurysms only and with angles excluded, were also performed. In a multivariable conditional logistic regression model we showed that smaller diameter size ratio (OR 0.0004, 95% CI 0.0001-0.15), larger daughter-daughter angles (OR 1.08, 95% CI 1.06-1.11) and larger parent-daughter angle ratios (OR 4.24, 95% CI 1.77-10.16) were significantly associated with MCA aneurysm presence after correcting for other variables. In order to account for possible changes to the vasculature by the aneurysm, a subgroup analysis of small aneurysms (≤ 3 mm) was performed and showed that the results were similar.

Conclusions: Easily measurable morphological parameters of the surrounding vasculature of the MCA may provide objective metrics to assess MCA aneurysm formation risk in high-risk patients.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2021.106268DOI Listing
December 2021

Screening for Preclinical Parenchymal Lung Disease in Rheumatoid Arthritis.

Rheumatology (Oxford) 2021 Dec 7. Epub 2021 Dec 7.

Department of Medicine, Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Objectives: Pulmonary disease is a common extraarticular manifestation of rheumatoid arthritis (RA) associated with increased morbidity and mortality. No current strategies exist for screening this at-risk population for parenchymal lung disease, including emphysema and interstitial lung disease (ILD).

Methods: RA patients without a diagnosis of ILD or chronic obstructive pulmonary disease underwent prospective and comprehensive clinical, laboratory, functional, and radiologic evaluations. High resolution computed tomography (HRCT) scans were scored for preclinical emphysema and preclinical ILD and evaluated for other abnormalities.

Results: Pulmonary imaging and/or functional abnormalities were identified in 78 (74%) of 106 subjects; 45% had preclinical parenchymal lung disease. These individuals were older with lower diffusion capacity but had similar smoking histories compared with no disease. Preclinical emphysema (36%), the most commonly detected abnormality, was associated with older age, higher anti-cyclic citrullinated peptide antibody titers, and diffusion abnormalities. A significant proportion of preclinical emphysema occurred amongst never smokers (47%) with a predominantly panlobular pattern. Preclinical ILD (15%) was not associated with clinical, laboratory, or functional measures.

Conclusion: We identified a high prevalence of undiagnosed preclinical parenchymal lung disease in RA driven primarily by isolated emphysema, suggesting that it may be a prevalent and previously unrecognized pulmonary manifestation of RA, even amongst never smokers. As clinical, laboratory, and functional evaluations did not adequately identify preclinical parenchymal abnormalities, HRCT may be the most effective screening modality currently available for patients with RA.
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http://dx.doi.org/10.1093/rheumatology/keab891DOI Listing
December 2021

Dr. Kremer et al reply.

J Rheumatol 2021 Oct 15. Epub 2021 Oct 15.

Albany Medical College, Albany, New York; University of Massachusetts School of Medicine, Worcester, Massachusetts; Columbia University College of Physicians and Surgeons, New York, New York; Brigham and Women's Hospital, Boston, Massachusetts; New York University School of Medicine, New York, New York, USA. This study was supported by the Corrona Research Foundation, a not-for-profit 501(c)3 United States foundation. The authors declare no conflicts of interest relevant to this article. Address correspondence to Dr. J.M. Kremer, MD, 16 Hillard Lane, Latham, NY 12110, USA. Email:

Drs. Pincus, Bergman, and Yazici have raised some concerns about our published article comparing the Clinical Disease Activity Index (CDAI) with simultaneous measures of the Routine Assessment of Patient Index Data 3 (RAPID3). We believe our publication has clearly established that the validated CDAI scores provide a fundamentally different evaluation of disease status compared with the RAPID3.
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http://dx.doi.org/10.3899/jrheum.210992DOI Listing
October 2021

Prevalence and risk factors of bronchiectasis in rheumatoid arthritis: A systematic review and meta-analysis.

Semin Arthritis Rheum 2021 10 20;51(5):1067-1080. Epub 2021 Aug 20.

Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, 60 Fenwood Road, 6016U, Boston, MA 02115, United States; Harvard Medical School, Boston, MA, United States. Electronic address:

Objectives: We performed a systematic review and meta-analysis for the prevalence and risk factors of rheumatoid arthritis-related bronchiectasis (RA-BR).

Methods: We queried PubMed and EMBASE databases to identify published literature related to prevalence and risk factors for RA-BR among patients with RA. Data extraction included study design, country, year, method of RA-BR detection, RA characteristics, numerator of RA-BR cases and denominator of patients with RA, and associations with RA-BR presence. We performed a meta-analysis using random or fixed effects models to estimate the prevalence of RA-BR among RA.

Results: Out of a total of 253 studies, we identified 41 total studies that reported on prevalence (n = 34), risk factors (n = 5), or both (n = 2). The included studies had heterogeneous methods to identify RA-BR. Among the 36 studies reporting prevalence, 608 RA-BR cases were identified from a total of 8569 patients with RA. In the meta-analysis, the pooled overall prevalence of RA-BR among RA was 18.7% (95%CI 13.7-24.3%) using random effects and 3.8% (95%CI 3.3-4.2%) using fixed effects. Among studies that used high-resolution chest computed tomography (HRCT) imaging, the prevalence of RA-BR was 22.6% (95%CI 16.8-29.0%) using random effects. When only considering retrospective studies (n = 12), the pooled prevalence of RA-BR among RA was 15.5% (95%CI 7.5-25.5%); among prospective studies (n = 24), the pooled prevalence was 20.7% (95% CI 14.7-27.4%). Risk factors for RA-BR included older age, longer RA duration, genetics (CFTR and HLA), and undetectable circulating mannose binding lectin (MBL) as a biomarker.

Conclusion: In this systematic review and meta-analysis, the prevalence of RA-BR was nearly 20% among studies with HRCT imaging, suggesting that bronchiectasis may be a common extra-articular feature of RA. Relatively few factors have been associated with RA-BR. Future studies should standardize methods to identify RA-BR cases and investigate the natural history and clinical course given the relatively high prevalence among RA.
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http://dx.doi.org/10.1016/j.semarthrit.2021.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453125PMC
October 2021

Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease.

Blood Adv 2021 09;5(17):3445-3456

Center for Cytokine Storm Treatment & Laboratory, Department of Medicine, University of Pennsylvania, Philadelphia, PA.

Idiopathic multicentric Castleman disease (iMCD) is a poorly understood hematologic disorder involving cytokine-induced polyclonal lymphoproliferation, systemic inflammation, and potentially fatal multiorgan failure. Although the etiology of iMCD is unknown, interleukin-6 (IL-6) is an established disease driver in approximately one-third of patients. Anti-IL-6 therapy, siltuximab, is the only US Food and Drug Administration-approved treatment. Few options exist for siltuximab nonresponders, and no validated tests are available to predict likelihood of response. We procured and analyzed the largest-to-date cohort of iMCD samples, which enabled classification of iMCD into disease categories, discovery of siltuximab response biomarkers, and identification of therapeutic targets for siltuximab nonresponders. Proteomic quantification of 1178 analytes was performed on serum of 88 iMCD patients, 60 patients with clinico-pathologically overlapping diseases (human herpesvirus-8-associated MCD, N = 20; Hodgkin lymphoma, N = 20; rheumatoid arthritis, N = 20), and 42 healthy controls. Unsupervised clustering revealed iMCD patients have heterogeneous serum proteomes that did not cluster with clinico-pathologically overlapping diseases. Clustering of iMCD patients identified a novel subgroup with superior response to siltuximab, which was validated using a 7-analyte panel (apolipoprotein E, amphiregulin, serum amyloid P-component, inactivated complement C3b, immunoglobulin E, IL-6, erythropoietin) in an independent cohort. Enrichment analyses and immunohistochemistry identified Janus kinase (JAK)/signal transducer and activator of transcription 3 signaling as a candidate therapeutic target that could potentially be targeted with JAK inhibitors in siltuximab nonresponders. Our discoveries demonstrate the potential for accelerating discoveries for rare diseases through multistakeholder collaboration.
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http://dx.doi.org/10.1182/bloodadvances.2020004016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8525223PMC
September 2021

Predictors of rheumatic immune-related adverse events and de novo inflammatory arthritis after immune checkpoint inhibitor treatment for cancer.

Arthritis Rheumatol 2021 Aug 16. Epub 2021 Aug 16.

Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, MA, USA.

Objective: To identify predictors of rheumatic immune-related adverse events (rheum-irAEs) after immune checkpoint inhibitor (ICI) treatment for cancer.

Methods: We performed a case-control study to predict rheum-irAEs at Mass General Brigham and Dana-Farber Cancer Institute (2011-2020). We screened for rheum-irAEs by reviewing patients evaluated by rheumatology or prescribed non-glucocorticoid immunomodulators (IM) after ICI (baseline). Medical review confirmed the presence of rheum-irAEs and indication for IM. Controls lacked rheum-irAEs (had no glucocorticoid use, rheumatology evaluation, IM use, and survived 6 months after baseline). We used logistic regression to estimate odds ratios (ORs) of the baseline predictors of rheum-irAEs.

Results: We identified 8,028 ICI recipients (mean age 65.5 years, 43.1% female, and 31.8% with lung cancer). After ICI, 404 (5.0%) were evaluated by rheumatology and 475 (5.9%) received an IM to treat any irAE. There were 226 (2.8%) confirmed rheum-irAE cases and 118 (1.5%) had de novo inflammatory arthritis. Rheumatic diseases (either pre-existing or rheum-irAEs) were a leading indication for IM use (27.9%). Baseline predictors of rheum-irAEs included melanoma (multivariable OR 4.06, 2.54-6.51) and genitourinary cancer (OR 2.22, 1.39-3.54; ref=lung cancer), combination ICI (OR 2.35, 1.48-3.74; ref=PD-1 inhibitor monotherapy), autoimmune disease (OR 2.04, 1.45-2.85), and recent glucocorticoid use (OR 2.13, 1.51-2.98; ref=no use) compared to 2,312 controls without rheum-irAEs. Predictors of de novo inflammatory arthritis were similar.

Conclusion: We identified novel predictors of rheum-irAEs that included melanoma, genitourinary cancer, pre-existing autoimmune disease, combination ICI, and glucocorticoid use. The proportion of cancer patients experiencing rheum-irAEs may be even higher than we report since we used stringent criteria to identify cases. These findings may identify cancer patients at risk of developing rheum-irAEs and de novo inflammatory arthritis and inform pathogenesis.
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http://dx.doi.org/10.1002/art.41949DOI Listing
August 2021

Tobacco use and age are associated with different morphologic features of anterior communicating artery aneurysms.

Sci Rep 2021 02 26;11(1):4791. Epub 2021 Feb 26.

Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA.

We present a cohort of patients with anterior communicating artery (ACoA) aneurysms to investigate morphological characteristics and clinical factors associated with rupture of the aneurysms. 505 patients with ACoA aneurysms were identified at the Brigham and Women's Hospital and Massachusetts General Hospital between 1990 and 2016, with available CT angiography (CTA). Three-dimensional (3D) reconstructions were performed to evaluate aneurysmal morphologic features, including location, projection, irregularity, the presence of daughter dome, height, height/width ratio, and relationships between surrounding vessels. Patient risk factors assessed included patient age, sex, tobacco use, alcohol use, and family history of aneurysms and aneurysmal subarachnoid hemorrhage. Logistic regression was used to build a predictive ACoA score for rupture. Morphologic features associated with ruptured ACoA aneurysms were the presence of a daughter dome (OR 21.4, 95% CI 10.6-43.1), smaller neck diameter (OR 0.55, 95% CI 0.42-0.71), larger aspect ratio (OR 3.57, 95% CI 2.05-6.24), larger flow angle (OR 1.03, 95% CI 1.02-1.05), and smaller ipsilateral A2-ACoA angle (OR 0.98, 95% CI 0.97-1.00). Tobacco use was predominantly associated with morphological factors intrinsic to the aneurysm that were associated with rupture while younger age was also associated with morphologic features extrinsic to the aneurysm that were associated with rupture. The ACoA score had good predictive capacity for rupture with AUC = 0.92 using the 0.632 bootstrap cross-validation for correction of overfitting bias. Ruptured ACoA aneurysms were associated with morphological features that are simple to assess using a simple scoring system. Tobacco use and younger age were predominantly associated with intrinsic and extrinsic morphological features characteristic of rupture, respectively.
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http://dx.doi.org/10.1038/s41598-021-84315-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910488PMC
February 2021

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

Arthritis Rheumatol 2021 06 9;73(6):970-979. Epub 2021 May 9.

Brigham and Women's Hospital, Harvard Medical School, and VA Boston Healthcare System, Boston, Massachusetts.

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.
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http://dx.doi.org/10.1002/art.41613DOI Listing
June 2021

Morphological variables associated with ruptured basilar tip aneurysms.

Sci Rep 2021 01 28;11(1):2526. Epub 2021 Jan 28.

Department of Neurosurgery, Brigham and Women's Hospital, 75 Francis Street, Boston, MA, 02115, USA.

Morphological factors of intracranial aneurysms and the surrounding vasculature could affect aneurysm rupture risk in a location specific manner. Our goal was to identify image-based morphological parameters that correlated with ruptured basilar tip aneurysms. Three-dimensional morphological parameters obtained from CT-angiography (CTA) or digital subtraction angiography (DSA) from 200 patients with basilar tip aneurysms diagnosed at the Brigham and Women's Hospital and Massachusetts General Hospital between 1990 and 2016 were evaluated. We examined aneurysm wall irregularity, the presence of daughter domes, hypoplastic, aplastic or fetal PCoAs, vertebral dominance, maximum height, perpendicular height, width, neck diameter, aspect and size ratio, height/width ratio, and diameters and angles of surrounding parent and daughter vessels. Univariable and multivariable statistical analyses were performed to determine statistical significance. In multivariable analysis, presence of a daughter dome, aspect ratio, and larger flow angle were significantly associated with rupture status. We also introduced two new variables, diameter size ratio and parent-daughter angle ratio, which were both significantly inversely associated with ruptured basilar tip aneurysms. Notably, multivariable analyses also showed that larger diameter size ratio was associated with higher Hunt-Hess score while smaller flow angle was associated with higher Fisher grade. These easily measurable parameters, including a new parameter that is unlikely to be affected by the formation of the aneurysm, could aid in screening strategies in high-risk patients with basilar tip aneurysms. One should note, however, that the changes in parameters related to aneurysm morphology may be secondary to aneurysm rupture rather than causal.
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http://dx.doi.org/10.1038/s41598-021-81364-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844275PMC
January 2021

Geometric variations associated with posterior communicating artery aneurysms.

J Neurointerv Surg 2021 Nov 21;13(11):1049-1052. Epub 2021 Jan 21.

Neurosurgery, Brigham and Women's Hospital, Boston, Massachusetts, USA

Background: Hemodynamic stress, conditioned by the morphology of the surrounding vasculature, plays an important role in aneurysm formation. Our goal was to identify image-based location-specific parameters that are associated with posterior communicating artery (PCoA) aneurysms.

Methods: Three-dimensional morphological parameters obtained from CT angiography or digital subtraction angiography from 187 patients with unilateral PCoA aneurysms, diagnosed at the Brigham and Women's Hospital and Massachusetts General Hospital between 1990 and 2016, were evaluated. In order to control for genetic and clinical risk factors, we chose the contralateral unaffected PCoA as a control group. We examined diameters and angles of the surrounding parent and daughter vessels. Univariable and multivariable statistical analyses were performed to determine statistical significance. Sensitivity analyses with small aneurysms (≤5 mm) only and an unmatched analysis of 432 PCoA aneurysms and 197 control patients without PCoA aneurysms were also performed.

Results: In a multivariable conditional logistic regression model we showed that smaller diameter size ratio (OR 1.45×10, 95% CI 1.12×10 to 1.88×10) and larger daughter-daughter angle (OR 1.04, 95% CI 1.02 to 1.07) were significantly associated with PCoA aneurysm presence after correcting for other variables. In subgroup analyses of small aneurysms (≤5 mm) and in an unmatched analysis the significance and direction of these results were preserved.

Conclusions: Larger daughter-daughter angles and smaller diameter size ratio are significantly associated with the presence of PCoA aneurysms. These simple parameters can be utilized to guide the risk assessment for the formation of PCoA aneurysms in high risk patients.
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http://dx.doi.org/10.1136/neurintsurg-2020-017062DOI Listing
November 2021

Diminished cytokine-induced Jak/STAT signaling is associated with rheumatoid arthritis and disease activity.

PLoS One 2021 14;16(1):e0244187. Epub 2021 Jan 14.

The Feinstein Institute for Medical Research and Northwell Health, Manhasset, New York, United States of America.

Rheumatoid arthritis (RA) is a systemic and incurable autoimmune disease characterized by chronic inflammation in synovial lining of joints. To identify the signaling pathways involved in RA, its disease activity, and treatment response, we adapted a systems immunology approach to simultaneously quantify 42 signaling nodes in 21 immune cell subsets (e.g., IFNα→p-STAT5 in B cells) in peripheral blood mononuclear cells (PBMC) from 194 patients with longstanding RA (including 98 patients before and after treatment), and 41 healthy controls (HC). We found multiple differences between patients with RA compared to HC, predominantly in cytokine-induced Jak/STAT signaling in many immune cell subsets, suggesting pathways that may be associated with susceptibility to RA. We also found that high RA disease activity, compared to low disease activity, was associated with decreased (e.g., IFNα→p-STAT5, IL-10→p-STAT1) or increased (e.g., IL-6→STAT3) response to stimuli in multiple cell subsets. Finally, we compared signaling in patients with established, refractory RA before and six months after initiation of methotrexate (MTX) or TNF inhibitors (TNFi). We noted significant changes from pre-treatment to post-treatment in IFNα→p-STAT5 signaling and IL-10→p-STAT1 signaling in multiple cell subsets; these changes brought the aberrant RA signaling profiles toward those of HC. This large, comprehensive functional signaling pathway study provides novel insights into the pathogenesis of RA and shows the potential of quantification of cytokine-induced signaling as a biomarker of disease activity or treatment response.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244187PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808603PMC
April 2021

Validation of the adjusted multi-biomarker disease activity score as a prognostic test for radiographic progression in rheumatoid arthritis: a combined analysis of multiple studies.

Arthritis Res Ther 2021 01 4;23(1). Epub 2021 Jan 4.

Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, Netherlands.

Background: The multi-biomarker disease activity (MBDA) test measures 12 serum protein biomarkers to quantify disease activity in RA patients. A newer version of the MBDA score, adjusted for age, sex, and adiposity, has been validated in two cohorts (OPERA and BRASS) for predicting risk for radiographic progression. We now extend these findings with additional cohorts to further validate the adjusted MBDA score as a predictor of radiographic progression risk and compare its performance with that of other risk factors.

Methods: Four cohorts were analyzed: the BRASS and Leiden registries and the OPERA and SWEFOT studies (total N = 953). Treatments included conventional DMARDs and anti-TNFs. Associations of radiographic progression (ΔTSS) per year with the adjusted MBDA score, seropositivity, and clinical measures were evaluated using linear and logistic regression. The adjusted MBDA score was (1) validated in Leiden and SWEFOT, (2) compared with other measures in all four cohorts, and (3) used to generate curves for predicting risk of radiographic progression.

Results: Univariable and bivariable analyses validated the adjusted MBDA score and found it to be the strongest, independent predicator of radiographic progression (ΔTSS > 5) compared with seropositivity (rheumatoid factor and/or anti-CCP), baseline TSS, DAS28-CRP, CRP SJC, or CDAI. Neither DAS28-CRP, CDAI, SJC, nor CRP added significant information to the adjusted MBDA score as a predictor, and the frequency of radiographic progression agreed with the adjusted MBDA score when it was discordant with these measures. The rate of progression (ΔTSS > 5) increased from < 2% in the low (1-29) adjusted MBDA category to 16% in the high (45-100) category. A modeled risk curve indicated that risk increased continuously, exceeding 40% for the highest adjusted MBDA scores.

Conclusion: The adjusted MBDA score was validated as an RA disease activity measure that is prognostic for radiographic progression. The adjusted MBDA score was a stronger predictor of radiographic progression than conventional risk factors, including seropositivity, and its prognostic ability was not significantly improved by the addition of DAS28-CRP, CRP, SJC, or CDAI.
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http://dx.doi.org/10.1186/s13075-020-02389-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784276PMC
January 2021

The Clinical Disease Activity Index and the Routine Assessment of Patient Index Data 3 for Achievement of Treatment Strategies.

J Rheumatol 2021 Dec 15;48(12):1776-1783. Epub 2020 Dec 15.

K. Kane, MS, G. Reed, PhD, University of Massachusetts Medical School, Worcester, Massachusetts.

Objective: To compare the Clinical Disease Activity Index (CDAI) with the Routine Assessment of Patient Index Data 3 (RAPID3) from 2 large United States registries.

Methods: Using a cross section of clinic visits within 2 registries, we determined whether the outcome of each metric would place the patient in remission (REM), low (LDA), moderate (MDA), or high disease activity (HDA) using the CDAI, with the assumption that a patient in MDA or HDA would be a candidate for acceleration of treatment.

Results: We identified significant disparities between the 2 indices in final disease categorization using each index system. For patients identified in LDA by CDAI, RAPID3 identified 20.4% and 28.3% as LDA in Corrona and the Brigham and Women's Rheumatoid Arthritis Sequential Study (BRASS), respectively. For patients identified as MDA by CDAI, RAPID3 identified 36.2% and 31.1% as MDA in Corrona and BRASS, respectively, with the greatest disparities within each system identified for LDA and MDA activity by the CDAI (20.4% and 36.2% agreement of RAPID3 with CDAI, respectively, in Corrona and 28.3% and 31.1% agreement in BRASS). Overall comparison between CDAI and RAPID3 in the 4 disease categories resulted in estimated κ = 0.285 in both. The RAPID3 scores indicated the potential for treat-to-target acceleration in 34.4% of patients in REM or LDA based on CDAI in Corrona and 27.7% in BRASS, respectively.

Conclusion: The RAPID3, based on patient-reported outcomes, shows differences with CDAI categories of disease activity. The components of CDAI are not highly correlated with RAPID3, except for patient global assessment. These differences could significantly affect the decision to advance treatment when using a treat-to-target regimen.
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http://dx.doi.org/10.3899/jrheum.200692DOI Listing
December 2021

Vascular Geometry Associated with Anterior Communicating Artery Aneurysm Formation.

World Neurosurg 2021 02 9;146:e1318-e1325. Epub 2020 Dec 9.

Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. Electronic address:

Objective: To identify clinical and morphologic risk factors correlated with anterior communicating artery (ACoA) aneurysm formation.

Methods: Three-dimensional morphologic parameters obtained from computed tomography angiography or digital subtraction angiography from 504 patients with ACoA aneurysms and 201 patients with aneurysms in other locations that were diagnosed at Brigham and Women's Hospital and Massachusetts General Hospital between 1990 and 2016 were evaluated. The presence of hypoplastic and aplastic A1 segments and diameters and angles of surrounding parent and daughter vessels were examined. Univariable and multivariable statistical analyses were performed to determine statistical significance. Sensitivity analyses for small (≤3 mm) aneurysms only were also performed.

Results: Aplastic and hypoplastic A1 segments were more common in the ACoA group (38.9% vs. 6.5% hypoplastic and 22.2% vs. 0.5% aplastic). In multivariable analysis, the presence of a hypoplastic A1 segment was associated with ACoA aneurysms. An A2-ACoA (daughter-daughter) angle was also significantly associated with ACoA aneurysms in multivariable analysis; however, as Pearson's correlation test between aneurysm width and daughter-daughter angle was significant, the daughter-daughter angle was most likely not independently associated with aneurysm presence, but rather might have been a result of the presence of an aneurysm. Subgroup analyses of small aneurysms (≤3 mm) and of unruptured aneurysms showed similar results.

Conclusions: Our results demonstrate that of all the morphologic parameters, the presence of a hypoplastic A1 segment was the only parameter independently associated with the presence of ACoA aneurysms that was not correlated with aneurysm size and could aid as a simple screening parameter.
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http://dx.doi.org/10.1016/j.wneu.2020.11.160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897254PMC
February 2021

Lifestyle and Clinical Risk Factors for Incident Rheumatoid Arthritis-associated Interstitial Lung Disease.

J Rheumatol 2021 05 15;48(5):656-663. Epub 2020 Nov 15.

W. Huang, MSPH, P.F. Dellaripa, MD, S. Huang, MD, MS, V. Feathers, MS, B. Lu, MD, DrPH, M.E. Weinblatt, MD, N.A. Shadick, MD, MPH, J.A. Sparks, MD, MMSc, Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston;

Objective: To determine the association between novel lifestyle factors on risk of rheumatoid arthritis (RA)-associated interstitial lung disease (ILD), define the threshold at which smoking increases RA-ILD risk, and calculate the degree to which known lifestyle and clinical factors predict RA-ILD.

Methods: This nested case-control study matched incident RA-ILD cases to RA non-ILD controls on age, sex, RA duration, rheumatoid factor, and time from exposure assessment to RA-ILD. Exposures included education, BMI, smoking, anticyclic citrullinated peptide antibodies, race, joint erosions, rheumatoid nodules, C-reactive protein (CRP), disease activity score, functional status, disease-modifying antirheumatic drug use, and glucocorticoid use. OR for each exposure on risk of RA-ILD were obtained from logistic regression models. Area under the curve (AUC) was calculated based on all lifestyle and clinical exposures.

Results: We identified 84 incident RA-ILD cases and 233 matched controls. After adjustment, obesity, high-positive CRP (≥ 10 mg/L), and poor functional status (multidimensional Health Assessment Questionnaire [MDHAQ] ≥ 1) were associated with increased risk of RA-ILD (OR 2.42, 95% CI 1.11-5.24 vs normal BMI; OR 2.61, 95% CI 1.21-5.64 vs CRP < 3 mg/L; OR 3.10, 95% CI 1.32-7.26 vs MDHAQ < 0.2). Smoking 30 pack-years or more was strongly associated with risk of RA-ILD compared to never smokers (OR 6.06, 95% CI 2.72-13.5). Together, lifestyle and clinical risk factors for RA-ILD had an AUC of 0.79 (95% CI 0.73-0.85).

Conclusion: Obesity, CRP, functional status, and extensive smoking may be novel risk factors for RA-ILD that may be useful for RA-ILD risk assessment and prevention. The overall ability to predict RA-ILD remains modest.
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http://dx.doi.org/10.3899/jrheum.200863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096643PMC
May 2021

Surrounding vascular geometry associated with basilar tip aneurysm formation.

Sci Rep 2020 10 21;10(1):17928. Epub 2020 Oct 21.

Department of Neurosurgery, Brigham and Women's Hospital, 75 Francis Street, Boston, MA, 02115, USA.

Hemodynamic stress is thought to play an important role in the formation of intracranial aneurysms, which is conditioned by the geometry of the surrounding vasculature. Our goal was to identify image-based morphological parameters that were associated with basilar artery tip aneurysms (BTA) in a location-specific manner. Three-dimensional morphological parameters obtained from CT-angiography (CTA) or digital subtraction angiography (DSA) from 207 patients with BTAs and a control group of 106 patients with aneurysms elsewhere to control for non-morphological factors, who were diagnosed at the Brigham and Women's Hospital and Massachusetts General Hospital between 1990 and 2016, were evaluated. We examined the presence of hypoplastic, aplastic or fetal PCoAs, vertebral dominance, and diameters and angles of surrounding parent and daughter vessels. Univariable and multivariable statistical analyses were performed to determine statistical significance. Sensitivity analyses with small (≤ 3 mm) aneurysms only and with angles excluded, were also performed. In multivariable analysis, daughter-daughter angle was directly, and parent artery diameter and diameter size ratio were inversely associated with BTAs. These results remained significant in the subgroup analysis of small aneurysms (width ≤ 3 mm) and when angles were excluded. These easily measurable and robust parameters that are unlikely to be affected by aneurysm formation could aid in risk stratification for the formation of BTAs in high-risk patients.
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http://dx.doi.org/10.1038/s41598-020-74266-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578056PMC
October 2020

Rheumatoid arthritis-related lung disease detected on clinical chest computed tomography imaging: Prevalence, risk factors, and impact on mortality.

Semin Arthritis Rheum 2020 12 28;50(6):1216-1225. Epub 2020 Sep 28.

Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, 60 Fenwood Road, Boston, MA 02115, United States; Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, United States. Electronic address:

Objective: We aimed to determine the real-world prevalence and investigate risk factors for rheumatoid arthritis (RA)-related lung disease on chest computed tomography (CT) imaging. We also investigated the impact of RA-related lung disease on mortality.

Methods: We studied chest CT imaging abnormalities among RA patients. We determined the presence and type of abnormalities using the chest CT imaging radiologic report. RA-related lung disease was defined as interstitial lung disease (ILD), bronchiectasis, or pleural disease. We examined whether demographics and RA characteristics were associated with RA-related lung disease using logistic regression. RA-related lung disease and mortality was described using survival curves and Cox regression.

Results: We analyzed 190 patients who had chest CT imaging performed for clinical indications. Mean age was 64.2 years (SD 11.8), 80.0% were female, and 75.3% were seropositive. RA-related lung disease was detected in 54 patients (28.4%); 30 (15.8%) had ILD, 27 (14.2%) had bronchiectasis, and 18 (9.5%) had pleural disease. RA-related lung disease was reported in both seropositive and seronegative RA (28.7% vs. 27.7%, p = 1.00). Male sex (OR 2.62, 95%CI 1.17-5.88) and current methotrexate use (OR 2.73, 95%CI 1.27-5.61 vs. not current) were associated with RA-related lung disease. Twenty-four (44.4%) patients with RA-related lung disease died during mean 7.0 years of follow-up. RA-related lung disease had HR of 5.35 (95%CI 0.72-39.9) for mortality compared to normal chest CT.

Conclusions: In this real-world study, RA-related lung disease was commonly detected on chest CT imaging regardless of RA serostatus. RA-related lung disease had high mortality, emphasizing the importance in close monitoring of these patients.
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http://dx.doi.org/10.1016/j.semarthrit.2020.08.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736489PMC
December 2020

Data-Driven Patient Clustering and Differential Clinical Outcomes in the Brigham and Women's Rheumatoid Arthritis Sequential Study Registry.

Arthritis Care Res (Hoboken) 2021 04 13;73(4):471-480. Epub 2021 Mar 13.

Brigham and Women's Hospital, Boston, Massachusetts.

Objective: To use unbiased, data-driven, principal component (PC) and cluster analysis to identify patient phenotypes of rheumatoid arthritis (RA) that might exhibit distinct trajectories of disease progression, response to treatment, and risk for adverse events.

Methods: Patient demographic, socioeconomic, health, and disease characteristics recorded at entry into a large, single-center, prospective observational registry cohort, the Brigham and Women's Rheumatoid Arthritis Sequential Study (BRASS), were harmonized using PC analysis to reduce dimensionality and collinearity. The number of PCs was established by eigenvalue >1, cumulative variance, and interpretability. The resulting PCs were used to cluster patients using a K-means approach. Longitudinal clinical outcomes were compared between the clusters over 2 years.

Results: Analysis of 142 variables from 1,443 patients identified 41 PCs that accounted for 77% of the cumulative variance in the data set. Cluster analysis distinguished 5 patient clusters: 1) less RA disease activity/multimorbidity, shorter RA duration, lower incidence of comorbidities; 2) less RA disease activity/multimorbidity, longer RA duration, more infections, psychiatric comorbidities, health care utilization; 3) moderate RA disease activity/multimorbidity, more neurologic comorbidity; 4) more RA disease activity/multimorbidity, shorter RA duration, more metabolic comorbidity, higher body mass index; 5) more RA disease activity/multimorbidity, longer RA duration, more hepatic, orthopedic comorbidity and RA-related surgeries. The clusters exhibited differences in clinical outcomes over 2 years of follow-up.

Conclusion: Data-driven analysis of the BRASS registry identified 5 distinct phenotypes of RA. These results illustrate the potential of data-driven patient profiling as a tool to support personalized medicine in RA. Validation in an independent data set is ongoing.
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http://dx.doi.org/10.1002/acr.24471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048846PMC
April 2021

Age and morphology of posterior communicating artery aneurysms.

Sci Rep 2020 07 14;10(1):11545. Epub 2020 Jul 14.

Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA.

Risk of intracranial aneurysm rupture could be affected by geometric features of intracranial aneurysms and the surrounding vasculature in a location specific manner. Our goal is to investigate the morphological characteristics associated with ruptured posterior communicating artery (PCoA) aneurysms, as well as patient factors associated with the morphological parameters. Three-dimensional morphological parameters in 409 patients with 432 PCoA aneurysms diagnosed at the Brigham and Women's Hospital and Massachusetts General Hospital between 1990 and 2016 who had available CT angiography (CTA) or digital subtraction angiography (DSA) were evaluated. Morphological parameters examined included aneurysm wall irregularity, presence of a daughter dome, presence of hypoplastic or aplastic A1 arteries and hypoplastic or fetal PCoA, perpendicular height, width, neck diameter, aspect and size ratio, height/width ratio, and diameters and angles of surrounding parent and daughter vessels. Univariable and multivariable statistical analyses were performed to determine the association of morphological parameters with rupture of PCoA aneurysms. Additional analyses were performed to determine the association of patient factors with the morphological parameters. Irregular, multilobed PCoA aneurysms with larger height/width ratios and larger flow angles were associated with ruptured PCoA aneurysms, whereas perpendicular height was inversely associated with rupture in a multivariable model. Older age was associated with lower aspect ratio, with a trend towards lower height/width ratio and smaller flow angle, features that are associated with a lower rupture risk. Morphological parameters are easy to assess and could help in risk stratification in patients with unruptured PCoA aneurysms. PCoA aneurysms diagnosed at older age have morphological features associated with lower risk.
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http://dx.doi.org/10.1038/s41598-020-68276-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360743PMC
July 2020

Correction to: Association of rheumatoid arthritis-related autoantibodies with pulmonary function test abnormalities in a rheumatoid arthritis registry.

Clin Rheumatol 2020 04;39(4):1371-1372

Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, 60 Fenwood Road, Boston, MA, 02115, USA.

The publisher regrets that the two sections under the Results omitted inadvertently on the original published version of the above article.
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http://dx.doi.org/10.1007/s10067-020-04968-xDOI Listing
April 2020

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

ACR Open Rheumatol 2019 Dec 24;1(10):620-626. Epub 2019 Oct 24.

Division of Rheumatology, Immunology & Allergy, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, 02115.

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 ( ) progressed to "often" 1 year later ( )).

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 ( = 0.0001, = 0.01, < 0.0001, respectively). Female RA patients developed more concentration complaints compared with males ( = 0.03); patients taking an anti-tumor necrosis factor therapy were less likely to complain of poor memory ( = 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.
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http://dx.doi.org/10.1002/acr2.11088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917307PMC
December 2019

Supplementing Claims Data with Electronic Medical Records to Improve Estimation and Classification of Rheumatoid Arthritis Disease Activity: A Machine Learning Approach.

ACR Open Rheumatol 2019 Nov 4;1(9):552-559. Epub 2019 Sep 4.

Brigham and Women's Hospital Boston Massachusetts.

Objective: Previous attempts to estimate rheumatoid arthritis (RA) disease activity using claims data only did not yield high performance. We aimed to assess whether supplementing claims data with readily available electronic medical record (EMR) data might result in improvement.

Methods: We used a subset of the Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study (BRASS) that had linked Medicare claims. The disease activity score in 28 joints with C-reactive protein (DAS28-CRP) was considered the gold standard of measure. Variables in the linked Medicare claims, as well as EMR recorded in the preceding one-year period were used as potential explanatory variables. We constructed three models: "Claims-Only," "Claims + Medications," and "Claims + Medications + Labs (laboratory data from EMR). We selected variables via adaptive LASSO. Model performance was measured with adjusted R2 for continuous DAS28-CRP and C-statistics for binary category classification (high/moderate vs low disease activity/remission).

Results: We identified 300 patients with laboratory data and linked Medicare claims. The mean age was 68 years and 80% were female. The mean (SD) DAS28-CRP was 3.6 (1.6) and 51% had high or moderate DAS28-CRP. For the continuous estimation, the adjusted R2 was 0.02 for Claims-Only, 0.09 for Claims + Medications, and 0.18 for Claims + Medications + Labs. The C-statistics for discriminating the binary categories were 0.61 for Claims-Only, 0.68 for Claims + Medications, and 0.76 for Claims + Medications + Labs.

Conclusion: Adding EMR-derived variables to claims-derived variables resulted in modest improvement. Even with EMR variables, we were unable to estimate continuous DAS28-CRP satisfactorily. However, in claims-EMR models, we were able to discriminate between binary categories of disease activity with reasonable accuracy.
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http://dx.doi.org/10.1002/acr2.11068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857973PMC
November 2019

Genetic associations with radiological damage in rheumatoid arthritis: Meta-analysis of seven genome-wide association studies of 2,775 cases.

PLoS One 2019 9;14(10):e0223246. Epub 2019 Oct 9.

Primary Care Centre Versus Arthritis, Research Institute for Primary Care and Health Sciences, Primary Care Sciences, Keele University, Keele, United Kingdom.

Background: Previous studies of radiological damage in rheumatoid arthritis (RA) have used candidate-gene approaches, or evaluated single genome-wide association studies (GWAS). We undertook the first meta-analysis of GWAS of RA radiological damage to: (1) identify novel genetic loci for this trait; and (2) test previously validated variants.

Methods: Seven GWAS (2,775 RA cases, of a range of ancestries) were combined in a meta-analysis. Radiological damage was assessed using modified Larsen scores, Sharp van Der Heijde scores, and erosive status. Single nucleotide polymophsim (SNP) associations with radiological damage were tested at a single time-point using regression models. Primary analyses included age and disease duration as covariates. Secondary analyses also included rheumatoid factor (RF). Meta-analyses were undertaken in trans-ethnic and European-only cases.

Results: In the trans-ethnic primary meta-analysis, one SNP (rs112112734) in close proximity to HLA-DRB1, and strong linkage disequilibrium with the shared-epitope, attained genome-wide significance (P = 4.2x10-8). In the secondary analysis (adjusting for RF) the association was less significant (P = 1.7x10-6). In both trans-ethnic primary and secondary meta-analyses 14 regions contained SNPs with associations reaching P<5x10-6; in the European primary and secondary analyses 13 and 10 regions contained SNPs reaching P<5x10-6, respectively. Of the previously validated SNPs for radiological progression, only rs660895 (tagging HLA-DRB1*04:01) attained significance (P = 1.6x10-5) and had a consistent direction of effect across GWAS.

Conclusions: Our meta-analysis confirms the known association between the HLA-DRB1 shared epitope and RA radiological damage. The lack of replication of previously validated non-HLA markers highlights a requirement for further research to deliver clinically-useful prognostic genetic markers.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0223246PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785117PMC
March 2020

Association of Seropositivity and Mortality in Rheumatoid Arthritis and the Impact of Treatment With Disease-Modifying Antirheumatic Drugs: Results From a Real-World Study.

Arthritis Care Res (Hoboken) 2020 02 13;72(2):176-183. Epub 2020 Jan 13.

Brigham and Women's Hospital, Boston, Massachusetts.

Objective: Seropositivity for anti-citrullinated protein antibody (ACPA)/rheumatoid factor (RF) in rheumatoid arthritis (RA) is associated with increased overall mortality; however, the association between antibody titers and mortality is not well established. Investigating relationships between antibody titers and mortality may clarify their role in RA pathogenesis. This study was undertaken to evaluate the association of antibody titers with mortality and its modification by disease-modifying antirheumatic drugs (DMARDs).

Methods: Eligible patients with established RA were identified through administrative claims data linked to laboratory results (2005-2016). Patients were categorized by positivity status for ACPA, RF, or both. Patients were further divided into groups by autoantibody titers. DMARD-exposed patients were categorized into biologic DMARD (bDMARD) and conventional DMARD (cDMARD) subcohorts. Crude mortality rates/1,000 patient-years and Kaplan-Meier curves were compared between antibody categories. Adjusted Cox proportional hazards regression and sensitivity (propensity-matched patients) analyses were conducted.

Results: Overall, 53,849 and 79,926 patients had evaluable ACPA and RF status, respectively. For both autoantibodies, mortality rates were significantly higher in seropositive versus seronegative patients (risk increase of 48.0% and 44.0% in ACPA- and RF-positive patients, respectively; P < 0.001 each). Mortality rates were greatest in patients with higher versus lower autoantibody titers (ACPA hazard ratio [HR] 1.60 [95% confidence interval (95% CI]) 1.45-1.76]; RF HR 1.78 [95% CI 1.66-1.91]). In cDMARD-exposed patients, HRs were higher in seropositive versus seronegative cohorts; in bDMARD-exposed patients, there was no difference in mortality by serostatus.

Conclusion: Elevated ACPA/RF titers were independently associated with increased mortality among patients with RA and persisted in patients treated with cDMARDs but not with bDMARDs.
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http://dx.doi.org/10.1002/acr.24071DOI Listing
February 2020

Association of rheumatoid arthritis-related autoantibodies with pulmonary function test abnormalities in a rheumatoid arthritis registry.

Clin Rheumatol 2019 12 13;38(12):3401-3412. Epub 2019 Aug 13.

Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, 60 Fenwood Road, Boston, MA, 02115, USA.

Introduction: We investigated whether rheumatoid arthritis (RA)-related autoantibodies were associated with abnormalities on pulmonary function tests (PFTs).

Methods: We studied RA serostatus and PFT abnormalities within a RA registry. RA serostatus was assessed by research assays for cyclic citrullinated peptide (CCP) and rheumatoid factor (RF). Outcomes were abnormalities on clinically indicated PFTs, including restriction, obstruction, and diffusion abnormality. Logistic regression was used to obtain ORs and 95% CIs for the PFT abnormalities by RA serologic phenotypes independent of lifestyle and RA characteristics.

Results: Among 1272 analyzed subjects, mean age was 56.3 years (SD 14.1), 82.2% were female, and 69.5% were seropositive. There were 100 subjects with abnormal PFTs. Compared with seronegativity, seropositivity was associated with increased odds of any PFT abnormality (multivariable OR 2.29, 95% CI 1.30-4.03). When analyzing type of PFT abnormality, seropositivity was also associated with restriction, obstruction, and diffusion abnormalities; multivariable ORs were 2.48 (95% CI 1.26-4.87), 3.12 (95% CI 1.28-7.61), and 2.30 (95% CI 1.09-4.83), respectively. When analyzing by CCP and RF status, the associations were stronger for RF+ than for CCP+ (any PFT abnormality OR 1.99, 95% CI 1.21-3.27 for RF+ vs. RF-; OR 1.67, 95% CI 1.03-2.69 for CCP+ vs. CCP-) with a dose effect of higher RF titer increasing odds for each PFT abnormality (p for trend < 0.05).

Conclusions: Seropositive RA patients had two-fold increased risk for abnormalities on PFTs performed for clinical indications compared with seronegative RA. Patients with seropositive RA, particularly those with high-titer RF positivity, may be more likely to have obstructive and restrictive abnormalities, independent of smoking.Key points• Due to the known excess pulmonary morbidity/mortality in RA, we studied the relationship of rheumatoid arthritis (RA)-related autoantibodies with pulmonary function test (PFT) abnormalities using a large RA registry.• We evaluated whether presence and levels of cyclic citrullinated peptide (CCP) and rheumatoid factor (RF) were associated with restriction, obstruction, and diffusion abnormalities on PFTs among 1272 subjects with RA.• Seropositivity was associated with two-fold increased risk for any PFT abnormality, independent of confounders including smoking. Higher titers of RF conferred greatest risk for all PFT outcomes: obstruction, restriction, and diffusion abnormality.• These results provide evidence that patients with RA should be closely monitored for pulmonary involvement, particularly those with high-titer RF seropositivity.
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http://dx.doi.org/10.1007/s10067-019-04733-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859190PMC
December 2019

The longitudinal effect of biologic use on patient outcomes (disease activity, function, and disease severity) within a rheumatoid arthritis registry.

Clin Rheumatol 2019 Nov 29;38(11):3081-3092. Epub 2019 Jul 29.

Brigham and Women's Hospital, 60 Fenwood Road, Boston, MA, 02115, USA.

Introduction: Biologics effectively manage symptoms and disease activity in rheumatoid arthritis (RA), but their long-term effects remain unclear.

Method: Longitudinal data were examined from the Brigham and Women's Rheumatoid Arthritis Sequential Study (BRASS) registry. Linear regression modeled the effect of biologic exposure on changes in disease activity (Disease Activity Score-28 with C-reactive protein [DAS28-CRP]), functional status (modified Health Assessment Questionnaire [mHAQ]), and RA severity (Routine Assessment of Patient Index Data [RAPID3]). Biologic exposure was the ratio of time on a biologic relative to time participating in the BRASS cohort.

Results: The analysis included 1395 RA patients, 82.3% female, with 6783 unique study visits from 2003 to 2015. At the patient's first visit, mean (SD) age was 56.3 (14.2) years and mean (SD) duration of RA was 12.7 (11.9) years. Average follow-up duration was 5.59 years (range, 1-13). Over time, DAS28-CRP, mHAQ, and RAPID3 scores decreased as the biologic exposure ratio increased. In repeated measures regression models, increased biologic exposure was significantly associated with decreased DAS28-CRP score (β = - 0.647; P < 0.001), decreased mHAQ score (β = - 0.096; P < 0.001), and decreased RAPID3 score (β = - 0.724; P < 0.001) during follow-up. Methotrexate use at baseline predicted decreased DAS28-CRP, mHAQ, and RAPID3 scores during follow-up. Biologic use at baseline predicted increased DAS28-CRP or mHAQ during follow-up.

Conclusions: Increased biologic exposure is associated with decreased disease activity, function impairment, and RA severity. Future studies should examine whether earlier initiation of biologics improves patient outcomes in RA.

Trial Registration: ClinicalTrials.gov , NCT01793103 Key Points • Biologics effectively manage symptoms and disease activity in rheumatoid arthritis (RA), but their long-term effects remain unclear. • In this analysis of longitudinal annual population samples of 1395 RA patients in the Brigham and Women's Rheumatoid Arthritis Sequential Study (BRASS) registry, disease activity, function, and severity scores improved as time on biologic therapy increased. • In repeated measures regression models, time on biologic therapy was a significant predictor of improved outcomes for disease activity, function, and RA severity. • Further studies should examine whether earlier initiation of biologics limits the long-term effect of inflammation on RA outcomes.
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http://dx.doi.org/10.1007/s10067-019-04649-4DOI Listing
November 2019

Correlates of Successful Rheumatoid Arthritis Flare Management: Clinician-driven Treatment, Home-based Strategies, and Medication Change.

J Rheumatol 2020 03 15;47(3):333-340. Epub 2019 Jun 15.

From the Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Division of Rheumatology, Hospital for Special Surgery, New York, New York; Division of Rheumatology and Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Objective: Describe strategies used to manage rheumatoid arthritis (RA) flares that contribute to a successful postflare outcome.

Methods: Data were collected from the BRASS registry, including clinical and patient-reported outcomes, and a survey with a Likert scale assessing postflare symptoms (better, unchanged, or worse). A logistic regression analysis adjusting for age, sex, flare number in the past 6 months, flare pain severity, home management, clinical consultation, and medication change was performed to evaluate factors influencing flare outcome.

Results: Of 503 participants, 185 reported at least 1 flare that had resolved in the past 6 months, with median (interquartile range) 28-joint count Disease Activity Score based on C-reactive protein 3 score 2.1 (1.7-2.8). Compared with RA symptoms before the flare, 22 (12%) patients felt worse, 125 (68%) were unchanged, and 38 (20%) felt better. To manage flares, 72% of patients used home-based remedies, 23% sought clinical consultation, and 56% made medication change. Of 103 patients who changed medication, 70% did so without seeking clinical advice. Making a medication change (OR 3.48, 95% CI 1.68-7.21) and having lower flare pain (OR 0.83, 95% CI 0.71-0.97) were associated with better flare outcome.

Conclusion: Flares occur frequently even in patients with low disease activity. Independent of home-based or clinically guided care, making a medication change and having less severe pain during a flare were associated with better flare outcomes. Of interest, the decision to change medications was frequently made without clinical advice. Future studies might address how best to intervene when patients experience flares and whether patient-initiated medication changes have adverse outcomes.
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http://dx.doi.org/10.3899/jrheum.181160DOI Listing
March 2020

Interference of tumor necrosis factor inhibitor treatments on soluble tumor necrosis factor receptor 2 levels in rheumatoid arthritis.

Pract Lab Med 2019 Aug 3;16:e00122. Epub 2019 May 3.

Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, MA, USA.

Objective: Soluble Tumor Necrosis Factor Receptor II (sTNFR2) is used as a biomarker to study cardiovascular disease (CVD) in diverse populations. TNF inhibitors (TNFi's) are a common treatment for inflammatory conditions. The objective of this study was to examine whether TNFi use impacts measured sTNFR2 levels.

Methods: We studied blood samples from a cohort of RA patients with clinical data and high sensitivity-C-reactive protein (hsCRP) measurements. To assess for interference, we tested the entire cohort for the expected positive correlation between sTNFR2 and TNFi using Pearson correlations. We then performed Pearson correlations between sTNFR2 and TNFi and sequentially removed subjects on adalimumab, etanercept, and infliximab; if interference was occurring, no correlation would be observed between hsCRP and sTNFR2, and correlation would be restored by removing subjects on the treatment causing the interference.

Results: We studied 190 subjects, 84.2% female, 73.4% anti-CCP positive. All subjects with sTNFR2 level exceeding measurable level were on etanercept. The expected positive correlation between hsCRP and sTNFR2 was not observed when assessing the entire cohort, r = 0.05, p = 0.51. However, the expected correlation was restored only after excluding subjects on etanercept, r = 0.46, p < 0.0001, and not adalimumab or infliximab. ELISA for sTNFR2 was performed using etanercept only and demonstrated direct binding to sTNFR2.

Conclusions: Our data identified interference between etanercept and the TNFR2 assay. Of the TNFi's, only etanercept has a TNF-binding domain modeled after TNFR2. These data should be considered when designing studies using sTNFR2 in populations where etanercept is a treatment option.
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http://dx.doi.org/10.1016/j.plabm.2019.e00122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527918PMC
August 2019

Association of Changes in Anticitrullinated Protein Antibody Levels With Resource Use and Disease Activity Measures in Rheumatoid Arthritis Patients a US Observational Cohort.

Clin Ther 2019 06 23;41(6):1057-1065.e3. Epub 2019 May 23.

Department of Rheumatology, Brigham and Women's Hospital, Boston, MA, USA.

Purpose: Anticitrullinated protein antibody (ACPA) concentration, beyond ACPA positivity, is indicative of more aggressive radiographic progression in patients with rheumatoid arthritis (RA). However, there is limited information on the association of changes in ACPA with resource use measures and/or disease activity measures. We evaluate associations between changes in levels of ACPA and outcomes, including durable medical equipment (DME) use, hospitalizations, and disease activity, in patients with established RA.

Methods: Patients from the Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study who had ACPA measurements at baseline and month 12 were included. Changes in ACPA levels from baseline to month 12 were categorized as a decrease (<-10%), no change (-10% to +10%), or increase (>+10%). DME use and hospitalizations were assessed twice yearly using patient questionnaires; disease activity was assessed annually. Binary multivariate logistic regression was used to analyze the association between changes in ACPA levels and DME use and hospitalizations; linear regression was used to assess the association with disease activity.

Findings: Of 840 patients included in the analysis, 291 (34.6%), 266 (31.7%), and 283 (33.7%) had a decrease, no change, or increase in ACPA levels, respectively. A decrease in ACPA levels was associated with a reduction in DME use (adjusted odds ratio [aOR] = 0.64; 95% CI, 0.44-0.93; P = 0.02) and hospitalizations (aOR = 0.62; 95% CI, 0.41-0.95; P = 0.03) versus no change or increase. Adjusted mean changes in disease activity score in 28 joints (C-reactive protein), total and swollen joint counts, and pain scores were significantly greater in patients with decreased ACPA levels versus those with no change or increase (P < 0.05).

Implications: Among patients with RA, reductions in ACPA levels of >10% were associated with reductions in DME use, hospitalizations, and disease activity. ClinicalTrials.gov identifier: NCT01793103.
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http://dx.doi.org/10.1016/j.clinthera.2019.04.029DOI Listing
June 2019
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