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This paper is to examine the relationship between anti-cyclic citrullinated peptide (anti-CCP) antibody titers and the development of interstitial lung disease (ILD) in patients with and without rheumatoid arthritis (RA). A retrospective investigation was conducted on all adult patients tested for anti-CCP between January 1, 2007, and December 31, 2012, in a university healthcare system. Patients with specified exposures or conditions known to cause ILD were excluded. The prevalence of ILD was compared between those with and without a positive CCP. The study population was then divided into four titer groups based on anti-CCP titers: negative, low titer, moderate titer, high titer. Fisher’s exact tests compared the prevalence of ILD among the anti-CCP titer groups. Multivariate logistic regression examined the association between anti-CCP and ILD while controlling for confounders. These analyses were repeated in two subgroups: a “confirmed RA” subgroup and an “unconfirmed RA” subgroup. Two thousand and thirty patients met inclusion criteria and 453 of those had confirmed RA. Progressively higher anti-CCP titer groups developed an increasingly higher prevalence of ILD (p < 0.01). When adjusting for age, tobacco, and a diagnosis of RA, higher anti-CCP titer groups continued to correlate with an increased prevalence of ILD (OR 1.47, 95% CI 1.10–1.96, p < 0.001). This study is the first to show that progressively higher anti-CCP titers correlate with increasing prevalence of ILD, even when adjusting for confounders.

Hemodialysis for chronic kidney disease (CKD) relies on vascular access (VA) devices, such as arteriovenous fistulas (AVF), grafts (AVG), or catheters, to maintain blood flow. Nonetheless, unpredictable progressive vascular stenosis due to neointimal formation or complete occlusion from acute thrombosis remains the primary cause of mature VA failure. Despite emergent surgical intervention efforts, the lack of a reliable early detection tool significantly reduces patient outcomes and survival rates. This study introduces a soft, wearable device that continuously monitors blood flow for early detection of VA failure. Using thermal anemometry, integrated sensors noninvasively measure flow changes in large vessels. Bench testing with AVF and AVG models shows agreement with finite element analysis (FEA) simulations, while human and preclinical swine trials demonstrate the device’s sensitivity. Wireless adaptation could enable at-home monitoring, improving detection of VA-related complications and survival in CKD patients. Vascular access failure in subjects with chronic kidney diseases undergoing hemodialysis significantly reduces survival rates. Here, the authors introduce a portable device to detect early failure with high sensitivity and real-time thrombosis detection.

Background Early diffuse cutaneous systemic sclerosis (dcSSc) has the highest case fatality among rheumatic diseases. We report baseline characteristics, current immunosuppressive therapies, progression of skin and internal organ involvement, and mortality in a multicenter prospective cohort from the United States (US) of America. Methods We performed a longitudinal analysis of participants from 12 US centers, from April 2012 to July 2020. All participants had early dcSSc or were at-risk for dcSSc, with ≤2 years since the first non-Raynaud’s phenomenon (RP) symptom. Results Three hundred one patients were included with a baseline median disease duration of 1.2 years since RP and a mean modified skin score of 21.1 units. At baseline, 263 (87.3%) had definite dcSSc and 38 (12.7%) were classified as at-risk; 112 (49.6%) patients were positive for anti-RNA polymerase III antibodies. The median follow-up duration was 24.5 months (IQR = 10.3–40.7 months). One hundred ninety (63.1%) participants were treated with an immunosuppressive therapy, of which mycophenolate mofetil was most used at baseline and follow-up. Of 38 who were classified as at-risk at baseline, 27 (71%) went on to develop dcSSc; these patients were characterized by higher baseline mean HAQ-DI (0.8 versus 0.4, p = 0.05) and higher baseline mRSS (8.8 versus 4.4, p < 0.01) in comparison with those who remained as limited cutaneous SSc. In the overall cohort, 48 participants (21.1%) had clinically significant worsening of skin fibrosis, mainly occurring in the first year of follow-up; 41 (23.3%) had an absolute forced vital capacity decline of ≥10%. Twenty participants (6.6%) died, of which 18 died in the first 3 years of follow-up. Cardiac involvement (33.3%), gastrointestinal dysmotility (22.2%), and progressive interstitial lung disease (ILD) (16.7%) were the main causes of death. Conclusion This US cohort highlights the management of early SSc in the current era, demonstrating progression of skin and lung involvement despite immunosuppressive therapy and high mortality due to cardiac involvement.

Background The modified Rodnan skin score (mRSS), a measure of systemic sclerosis (SSc) skin thickness, is agnostic to inflammation and vasculopathy. Previously, we demonstrated the potential of neural network-based digital pathology applied to SSc skin biopsies as a quantitative outcome. Here, we leverage deep learning and histologic analyses of clinical trial biopsies to decipher SSc skin features ‘seen’ by artificial intelligence (AI). Methods Adults with diffuse cutaneous SSc ≤ 6 years were enrolled in an open-label trial of belumosudil [a Rho-associated coiled-coil containing protein kinase 2 (ROCK2) inhibitor]. Participants underwent serial mRSS and arm biopsies at week (W) 0, 24 and 52. Two blinded dermatopathologists scored stained sections (e.g., Masson’s trichrome, hematoxylin and eosin, CD3, α-smooth muscle actin) for 16 published SSc dermal pathological parameters. We applied our deep learning model to generate QIF signatures/biopsy and obtain ‘Fibrosis Scores’. Associations between Fibrosis Score and mRSS (Spearman correlation), and between Fibrosis Score and mRSS versus histologic parameters [odds ratios (OR)], were determined. Results Only ten patients were enrolled due to early study termination, and of those, five had available biopsies due to fixation issues. Median, interquartile range (IQR) for mRSS change (0–52 W) for the ten participants was -2 (-9—7.5) and for the five with biopsies was -2.5 (-11—7.5). The correlation between Fibrosis Score and mRSS was R = 0.3; p  = 0.674. Per 1-unit mRSS change (0–52 W), histologic parameters with the greatest associated changes were (OR, 95% CI, p -value): telangiectasia (2.01, [(1.31—3.07], 0.001), perivascular CD3 + (0.99, [0.97—1.02], 0.015), and % of CD8 + among CD3 + (0.95, [0.89—1.01], 0.031). Likewise, per 1-unit Fibrosis Score change, parameters with greatest changes were (OR, p -value): hyalinized collagen (1.1, [1.04 – 1.16], < 0.001), subcutaneous (SC) fat loss (1.47, [1.19—1.81], < 0.001), thickened intima (1.21, [1.06—1.38], 0.005), and eccrine entrapment (1.14, [1—1.31], 0.046). Conclusions Belumosudil was associated with non-clinically meaningful mRSS improvement. The histologic features that significantly correlated with Fibrosis Score changes ( e.g., hyalinized collagen, SC fat loss) were distinct from those associated with mRSS changes ( e.g., telangiectasia and perivascular CD3 +). These data suggest that AI applied to SSc biopsies may be useful for quantifying pathologic features of SSc beyond skin thickness.

Background Skin fibrosis is the clinical hallmark of systemic sclerosis (SSc), where collagen deposition and remodeling of the dermis occur over time. The most widely used outcome measure in SSc clinical trials is the modified Rodnan skin score (mRSS), which is a semi-quantitative assessment of skin stiffness at seventeen body sites. However, the mRSS is confounded by obesity, edema, and high inter-rater variability. In order to develop a new histopathological outcome measure for SSc, we applied a computer vision technology called a deep neural network (DNN) to stained sections of SSc skin. We tested the hypotheses that DNN analysis could reliably assess mRSS and discriminate SSc from normal skin. Methods We analyzed biopsies from two independent (primary and secondary) cohorts. One investigator performed mRSS assessments and forearm biopsies, and trichrome-stained biopsy sections were photomicrographed. We used the AlexNet DNN to generate a numerical signature of 4096 quantitative image features (QIFs) for 100 randomly selected dermal image patches/biopsy. In the primary cohort, we used principal components analysis (PCA) to summarize the QIFs into a Biopsy Score for comparison with mRSS. In the secondary cohort, using QIF signatures as the input, we fit a logistic regression model to discriminate between SSc vs. control biopsy, and a linear regression model to estimate mRSS, yielding Diagnostic Scores and Fibrosis Scores, respectively. We determined the correlation between Fibrosis Scores and the published Scleroderma Skin Severity Score (4S) and between Fibrosis Scores and longitudinal changes in mRSS on a per patient basis. Results In the primary cohort ( n  = 6, 26 SSc biopsies), Biopsy Scores significantly correlated with mRSS (R = 0.55, p  = 0.01). In the secondary cohort ( n  = 60 SSc and 16 controls, 164 biopsies; divided into 70% training and 30% test sets), the Diagnostic Score was significantly associated with SSc-status (misclassification rate = 1.9% [training], 6.6% [test]), and the Fibrosis Score significantly correlated with mRSS (R = 0.70 [training], 0.55 [test]). The DNN-derived Fibrosis Score significantly correlated with 4S (R = 0.69, p  = 3 × 10 − 17 ). Conclusions DNN analysis of SSc biopsies is an unbiased, quantitative, and reproducible outcome that is associated with validated SSc outcomes.

The objective of this analysis is to examine whether the severity of systemic sclerosis (SSc)-hand involvement influences patient-reported outcome measure (PROM) completion rate in a US cohort of early disease. Participants included SSc patients with less than 5 years disease duration consented and enrolled in the Collaborative, National, Quality, and Efficacy Registry (CONQUER) between June 2018 and December 2019. Participants’ socio-demographics, hand clinical features (severe modified Rodnan skin score, presence of small joint contractures, acro-osteolysis, calcinosis, and digital ulcers), and completion rates of seven PROMs including a Resource Use Questionnaire were analyzed. Cohort characteristics and baseline PROM completion were evaluated. Multivariable logistic regression assessed the relationship between hand limitations and PROM incompletion at several time points using generalized estimating equations. At the time of data lock, 339 CONQUER subjects had a total of 600 visits available for analysis. Calcinosis (odds ratio [OR] 6.35, confidence interval [CI] 2.41–16.73 and acro-osteolysis OR 3.88 (1.57–9.55) were significantly associated with incomplete PROM. The Resource Use Questionnaire was the PROM most commonly not completed. Increasing age was correlated with resource use questionnaire incompletion rate. Acro-osteolysis and calcinosis were associated with lower PROM completion rates in a US SSc cohort, independent of the length of the questionnaires or the modality of administration (electronic or paper). Resource Use Questionnaires are important for understanding the economic impact and burden of chronic disease; however, in this study, it had lower completion rates than PROMs devoted to clinical variables.Key points•Multiple strategies are needed to ensure optimal completion of PROM in longitudinal cohort studies. Even if patients request electronic surveys, we have found it is important to follow up incomplete surveys with paper forms provided at the time of a clinical visit.•The Resource Utilization Questionnaire was lengthy and prone to non-completion in the younger population.•Acro-osteolysis and calcinosis were associated with reduced PROM completion rates.

Objective Although a high‐resolution computed tomography (HRCT) scan of the chest is the gold standard test for the detection of interstitial lung disease (ILD), there is no consensus among rheumatologists regarding the use of HRCT to screen for ILD in their patients with systemic sclerosis (SSc). The aims of this study were to describe the HRCT ordering practices at SSc centers in the United States and to determine which patient characteristics are associated with HRCT performance. Methods We performed a prospective cohort study of patients with SSc enrolled in the US‐based Collaborative National Quality and Efficacy Registry (CONQUER). We performed univariate logistic regression followed by multivariable logistic regression to determine which patient characteristics were associated with HRCT performance. Results Of the 356 patients with SSc enrolled in CONQUER, 286 (80.3%) underwent HRCT at some point during their disease course. On multivariable analyses, missing total lung capacity percent predicted (odds ratio [OR] 3.26, 95% confidence interval [CI]: 1.53‐7.41, P = 0.007) was positively associated with ever having undergone HRCT, whereas a positive anti‐centromere antibody (OR 0.27, 95% CI: 0.12‐0.61, P = 0.008) and missing forced vital capacity percent predicted (OR 0.29, 95% CI: 0.10‐0.80, P = 0.005) were negatively associated with ever having undergone HRCT. There was a trend toward a positive association between crackles on pulmonary exam and ever having undergone HRCT (OR 2.28, 95% CI: 0.97‐6.05, P = 0.058), although this relationship did not reach statistical significance. Conclusion The majority of patients with SSc enrolled in CONQUER underwent HRCT. A positive anti‐centromere antibody was the key clinical variable inversely associated with performance of HRCT.

Natalizumab is an efficacious agent for the induction and maintenance of remission in patients with Crohn's disease (CD) who have failed anti-tumor necrosis factor (TNF) agents. We aimed to assess the efficacy and safety of natalizumab outside of clinical trial at a US tertiary center. Retrospective case review of patients with CD receiving natalizumab. Forty-nine patients with CD (28 women; median age, 33 years) receiving natalizumab from April 2008 to November 2011 were identified. Median duration of disease was 180 months (range, 36-576 months); 40 patients had ileocolonic disease, 1 had ileal disease, and 8 had colonic disease. Twenty-one patients had penetrating disease, and 28 had a history of CD-related surgical treatment. Forty-seven patients previously failed treatment with at least 1 anti-TNF agent. Median duration of natalizumab treatment was 7 months (interquartile range, 3-21.5 months). Twenty-four patients (49%) were continuing natalizumab at the time of this review, and 25 discontinued treatment because of the lack of response, side effects, or positive JC virus antibody. Seventeen patients (35%) successfully continued treatment with natalizumab for longer than 12 months, and nonpenetrating disease phenotype was identified as a predictor of longer response (compared with penetrating phenotype; P = 0.013). Nine patients (18.4%) experienced adverse effects, 5 of which were serious, but no case of progressive multifocal leukoencephalopathy occurred. This is the largest series of natalizumab-treated patients with CD. Our results show that natalizumab is an efficacious and safe treatment agent for patients refractory to anti-TNF agents and that nonpenetrating disease phenotype has more durable response over time.

Natalizumab is an efficacious agent for the induction and maintenance of remission in patients with Crohn’s disease (CD) who have failed anti–tumor necrosis factor (TNF) agents. We aimed to assess the efficacy and safety of natalizumab outside of clinical trial at a US tertiary center.MethodsRetrospective case review of patients with CD receiving natalizumab.ResultsForty-nine patients with CD (28 women; median age, 33 years) receiving natalizumab from April 2008 to November 2011 were identified. Median duration of disease was 180 months (range, 36–576 months); 40 patients had ileocolonic disease, 1 had ileal disease, and 8 had colonic disease. Twenty-one patients had penetrating disease, and 28 had a history of CD-related surgical treatment. Forty-seven patients previously failed treatment with at least 1 anti-TNF agent. Median duration of natalizumab treatment was 7 months (interquartile range, 3–21.5 months). Twenty-four patients (49%) were continuing natalizumab at the time of this review, and 25 discontinued treatment because of the lack of response, side effects, or positive JC virus antibody. Seventeen patients (35%) successfully continued treatment with natalizumab for longer than 12 months, and nonpenetrating disease phenotype was identified as a predictor of longer response (compared with penetrating phenotype; P = 0.013). Nine patients (18.4%) experienced adverse effects, 5 of which were serious, but no case of progressive multifocal leukoencephalopathy occurred.ConclusionsThis is the largest series of natalizumab-treated patients with CD. Our results show that natalizumab is an efficacious and safe treatment agent for patients refractory to anti-TNF agents and that nonpenetrating disease phenotype has more durable response over time.