Citations

Objective We provide evidence‐based recommendations regarding the treatment of interstitial lung disease (ILD) in adults with systemic autoimmune rheumatic diseases (SARDs). Methods We developed clinically relevant population, intervention, comparator, and outcomes questions. A systematic literature review was then performed, and the available evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation methodology. A panel of clinicians and patients reached consensus on the direction and strength of the recommendations. Results Thirty‐five recommendations were generated (including two strong recommendations) for first‐line SARD‐ILD treatment, treatment of SARD‐ILD progression despite first‐line ILD therapy, and treatment of rapidly progressive ILD. The strong recommendations were against using glucocorticoids in systemic sclerosis–ILD as a first‐line ILD therapy and after ILD progression. Otherwise, glucocorticoids are conditionally recommended for first‐line ILD treatment in all other SARDs. Conclusion This clinical practice guideline presents the first recommendations endorsed by the American College of Rheumatology and American College of Chest Physicians for the treatment of ILD in people with SARDs.

Objective We provide evidence‐based recommendations regarding the treatment of interstitial lung disease (ILD) in adults with systemic autoimmune rheumatic diseases (SARDs). Methods We developed clinically relevant population, intervention, comparator, and outcomes questions. A systematic literature review was then performed, and the available evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation methodology. A panel of clinicians and patients reached consensus on the direction and strength of the recommendations. Results Thirty‐five recommendations were generated (including two strong recommendations) for first‐line SARD‐ILD treatment, treatment of SARD‐ILD progression despite first‐line ILD therapy, and treatment of rapidly progressive ILD. The strong recommendations were against using glucocorticoids in systemic sclerosis–ILD as a first‐line ILD therapy and after ILD progression. Otherwise, glucocorticoids are conditionally recommended for first‐line ILD treatment in all other SARDs. Conclusion This clinical practice guideline presents the first recommendations endorsed by the American College of Rheumatology and American College of Chest Physicians for the treatment of ILD in people with SARDs.

ObjectiveWe provide evidence‐based recommendations regarding screening for interstitial lung disease (ILD) and the monitoring for ILD progression in people with systemic autoimmune rheumatic diseases (SARDs), specifically rheumatoid arthritis, systemic sclerosis, idiopathic inflammatory myopathies, mixed connective tissue disease, and Sjögren disease.MethodsWe developed clinically relevant population, intervention, comparator, and outcomes questions related to screening and monitoring for ILD in patients with SARDs. A systematic literature review was performed, and the available evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation methodology. A Voting Panel of interdisciplinary clinician experts and patients achieved consensus on the direction and strength of each recommendation.ResultsFifteen recommendations were developed. For screening people with these SARDs at risk for ILD, we conditionally recommend pulmonary function tests (PFTs) and high‐resolution computed tomography of the chest (HRCT chest); conditionally recommend against screening with 6‐minute walk test distance (6MWD), chest radiography, ambulatory desaturation testing, or bronchoscopy; and strongly recommend against screening with surgical lung biopsy. We conditionally recommend monitoring ILD with PFTs, HRCT chest, and ambulatory desaturation testing and conditionally recommend against monitoring with 6MWD, chest radiography, or bronchoscopy. We provide guidance on ILD risk factors and suggestions on frequency of testing to evaluate for the development of ILD in people with SARDs.ConclusionThis clinical practice guideline presents the first recommendations endorsed by the American College of Rheumatology and American College of Chest Physicians for the screening and monitoring of ILD in people with SARDs.

Objective We provide evidence‐based recommendations regarding screening for interstitial lung disease (ILD) and the monitoring for ILD progression in people with systemic autoimmune rheumatic diseases (SARDs), specifically rheumatoid arthritis, systemic sclerosis, idiopathic inflammatory myopathies, mixed connective tissue disease, and Sjögren disease. Methods We developed clinically relevant population, intervention, comparator, and outcomes questions related to screening and monitoring for ILD in patients with SARDs. A systematic literature review was performed, and the available evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation methodology. A Voting Panel of interdisciplinary clinician experts and patients achieved consensus on the direction and strength of each recommendation. Results Fifteen recommendations were developed. For screening people with these SARDs at risk for ILD, we conditionally recommend pulmonary function tests (PFTs) and high‐resolution computed tomography of the chest (HRCT chest); conditionally recommend against screening with 6‐minute walk test distance (6MWD), chest radiography, ambulatory desaturation testing, or bronchoscopy; and strongly recommend against screening with surgical lung biopsy. We conditionally recommend monitoring ILD with PFTs, HRCT chest, and ambulatory desaturation testing and conditionally recommend against monitoring with 6MWD, chest radiography, or bronchoscopy. We provide guidance on ILD risk factors and suggestions on frequency of testing to evaluate for the development of ILD in people with SARDs. Conclusion This clinical practice guideline presents the first recommendations endorsed by the American College of Rheumatology and American College of Chest Physicians for the screening and monitoring of ILD in people with SARDs.

Introduction: Type 2 long QT syndrome (LQT2) is caused by loss-of-function variants in the KCNH2 -encoded K v 11.1 potassium channel which is essential for the rapid delayed rectifier channel (I Kr ) that governs phase 3 of cardiac action potential (AP). No current therapies target the molecular cause of LQT2. Methods: A dual-component “suppression-and-replacement” (SupRep) KCNH2 gene therapy was created by cloning into a single construct a custom-designed KCNH2 shRNA that produces ~80% knockdown (suppression) and a “shRNA-immune” (shIMM) KCNH2 cDNA modified by the introduction of synonymous single nucleotide substitutions within the shRNA target site (replacement). The ability of KCNH2-SupRep gene therapy to suppress and replace LQT2-causative variants in KCNH2 was evaluated via heterologous expression in TSA201 cells. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were generated from two patients with LQT2 (KCNH2-G604S and -N633S). CRISPR-Cas9 corrected isogenic control iPSC-CMs were made. Both lines were treated with KCNH2-SupRep or non-targeting control shRNA (shCT). FluoVolt voltage dye was used to measure the APD. Results: KCNH2-SupRep achieved mutation-independent suppression of wild-type KCNH2 and both LQT2-causative variants with simultaneous replacement of KCNH2-shIMM as measured by allele-specific qRT-PCR. Treatment with KCNH2-SupRep resulted in shortening of the pathologically prolonged APD at 90% repolarization (APD 90 ) to near isogenic control APD 90 levels (G604S: isogenic controls, 424 + 39 ms and N633S: isogenic controls, 433 + 16 ms) compared to treatment with non-targeting shCT (G604S: SupRep treated, 399±105 ms vs. shCT treated, 577±39 ms, p<0.0001; N633S: SupRep treated, 432±85 ms vs. shCT treated, 483±65 ms, p<0.005). Conclusions: We provide the first proof-of-principle gene therapy for correction of LQT2. Like our sentinel discovery of SupRep gene therapy for LQT1, KCNH2-SupRep successfully suppressed and replaced KCNH2 to normal wild-type levels. In TSA201 cells, co-transfection of LQT2 variants and KCNH2-SupRep caused mutation-independent suppression-and-replacement of KCNH2 . In LQT2 iPSC-CMs, KCNH2-SupRep shortened the APD, thereby eliminating the pathognomonic feature of LQT2.

Abstract Background Gangliosides are a family of complex lipids that are molecules composed of glycosphingolipid with one or more sialic acid linked on the sugar moieties. Gangliosides are recognized to play an important role in many biological processes and the alterations in ganglioside profiles have been observed in some neurodegenerative diseases, neuropathies and lysosomal disorders. Gangliosidoses are a group of inherited lysosomal enzyme deficiencies characterized by an accumulation of incompletely degraded gangliosides in the lysosome. While the diagnosis of gangliosidoses can be accomplished by measurement of enzymatic activities and/or molecular genetic testing, biomarker analysis could facilitate monitoring affected patients, including those enrolled in clinical trials of new treatment approaches (ie., substrate reduction or gene therapies). We developed a rapid and sensitive LC-MS/MS assay that allows simultaneous quantification of multiple gangliosides and other glycosphingolipids and tested it in serum and plasma of patients with a diagnosis of GM2-gangliosidosis. Methods Gangliosides and other glycosphingolipids were extracted from 20 µL serum or plasma using chloroform:methanol (1:2, v/v). A multiplexed LC-MS/MS assay was developed that targeted several ganglioside species (GM3, GM2, GM1, GD3, GD2, GD1, GT3, GT2, GT1 and GQ1) along with several glycosphingolipid species (GlcCer, LacCer, Gb3, Gb4 and GA2). This assay was performed on a triple quadrupole mass spectrometer with scheduled MRM in both negative and positive ion modes after internal standards (GM3 18:0-d5, GM1 17:0, GA2 17:0 and Gb3 18:0-d3) were spiked into clinical samples. Results The multiplexed targeted assay applied to serum and plasma from controls (47 and 49 samples, respectively) and three GM2-gangliosidosis patients for identification and quantification of the targeted gangliosides and other glycosphingolipids. The abundance of GM2 and GM1 gangliosides inserum and plasma of patients with GM2-gangliosidosis was significantly higher than in the control group (P &lt; 0.0001) whereas GM3 levels were significantly lower (P &lt; 0.005). Other gangliosides including GD3, GD2, GD1 and GT1 and glycosphingolipids such as GlcCer, LacCer and Gb3 were not significantly different between these patients and controls. Conclusion A multiplexed targeted assay for glycosphingolipids including gangliosides was developed. This assay will be further validated for potential use in the diagnosis and monitoring of patients with additional gangliosidoses.

Abstract Rationale In addition to rare genetic variants and the MUC5B locus, common genetic variants contribute to idiopathic pulmonary fibrosis (IPF) risk. The predictive power of common variants outside the MUC5B locus for IPF and interstitial lung abnormalities (ILAs) is unknown. Objectives We tested the predictive value of IPF polygenic risk scores (PRSs) with and without the MUC5B region on IPF, ILA, and ILA progression. Methods We developed PRSs that included (PRS-M5B) and excluded (PRS-NO-M5B) the MUC5B region (500-kb window around rs35705950-T) using an IPF genome-wide association study. We assessed PRS associations with area under the receiver operating characteristic curve (AUC) metrics for IPF, ILA, and ILA progression. Measurements and Main Results We included 14,650 participants (1,970 IPF; 1,068 ILA) from six multi-ancestry population-based and case–control cohorts. In cases excluded from genome-wide association study, the PRS-M5B (odds ratio [OR] per SD of the score, 3.1; P = 7.1 × 10−95) and PRS-NO-M5B (OR per SD, 2.8; P = 2.5 × 10−87) were associated with IPF. Participants in the top PRS-NO-M5B quintile had ∼sevenfold odds for IPF compared with those in the first quintile. A clinical model predicted IPF (AUC, 0.61); rs35705950-T and PRS-NO-M5B demonstrated higher AUCs (0.73 and 0.7, respectively), and adding both genetic predictors to a clinical model yielded the highest performance (AUC, 0.81). The PRS-NO-M5B was associated with ILA (OR, 1.25) and ILA progression (OR, 1.16) in European ancestry participants. Conclusions A common genetic variant risk score complements the MUC5B variant to identify individuals at high risk of interstitial lung abnormalities and pulmonary fibrosis.

Introduction: Calmodulin (CaM)-mediated long QT syndrome (CaM-LQTS) is a genetic arrhythmia disorder characterized by a high prevalence of life-threatening ventricular arrhythmias occurring very early in life, frequent T-wave alternans, markedly prolonged QT intervals (QTc > 600 ms), and intermittent 2:1 AV block. Three distinct genes ( CALM1 , CALM2 , and CALM3 ) all encode for the identical CaM protein. Conventional LQTS pharmacotherapies fail to adequately protect against potentially lethal cardiac events in patients with CaM-LQTS. Here, we developed a CALM1 “ suppression-replacement (SupRep)” gene therapy with the goal of rescuing the prolonged cardiac action potential duration (APD) and increased Ca 2+ amplitude (ΔF/F0) in patient-derived induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from a patient with CALM1 -mediated LQTS. Methods: Custom designed CALM1 -targeting shRNAs were tested for knockdown efficiency using TSA201 cells and RT-qPCR. A dual-component SupRep CALM1 gene therapy was created by cloning into a single construct a custom-designed CALM1 shRNA that produces knockdown (suppression) and a “shRNA-immune” (shIMM) CALM1 cDNA (replacement). Patient-specific CALM1-F142L iPSC-CMs were generated from a patient with severe LQTS (QTc = 515 ms). FluoVolt voltage-sensing dye was used to measure the APD at 90% repolarization (APD 90 ). Calcium transient amplitude was measured using Fluo-4 indicator. Results: Overall, 6 unique candidate CALM1 -targeting shRNAs were tested for knockdown efficiency in a transient transfection CALM1 over-expression TSA201 cell system. One candidate shRNA had an 80% knockdown efficiency of CALM1. Following transfection with CALM1 -SupRep gene therapy, the APD 90 was significantly decreased in F142L iPSC-CMs compared to untreated cells (F142L: 665 ± 9 ms [n=40] vs F142L + SupRep: 353 ± 9 ms [n=20], p<0.0001). Ca 2+ amplitude was significantly decreased following SupRep transfection when compared to untreated cells (0.99 ± 0.04 vs 0.8 ± 0.06, p=0.02). Conclusions: Here, we provide the first proof-of-principle SupRep gene therapy for CALM1-mediated LQTS. CALM1 -SupRep gene therapy shortened significantly the pathologically prolonged APD 90 in CALM1 -F142L patient-derived iPSC-CMs.

Introduction: Pathogenic variants in PKP2 -encoded plakophilin 2 cause arrhythmogenic right ventricular cardiomyopathy (ARVC). Electrocardiographically, PKP2 -mediated ARVC may mimic RYR2 -mediated catecholaminergic polymorphic ventricular tachycardia (CPVT). We compare the underlying mechanism of arrhythmia in ARVC and CPVT using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Methods: iPSC-CMs were generated from 2 ARVC patients with different PKP2 variants [E149X (PKP2-1) and c.2146-1G>C (PKP2-2)], 1 patient with a CPVT variant [RyR2-R176Q (CPVT1)], and a wild-type (WT) control. Fluo-4 AM calcium dye was used to assess calcium kinetics in iPSC-CMs before and during treatment with 100 nM isoproterenol (ISO) at 8-10 min. Results: Compared to WT, PKP2 and RYR2 iPSC-CMs had a greater amplitude before (WT: 0.331±0.031, PKP2-1: 1.048±0.074, PKP2-2: 1.076±0.095, CPVT1: 0.966±0.061; P<0.0001) and during ISO (WT: 0.277±0.022, PKP2-1: 0.971±0.069, PKP2-2: 0.622±0.041, CPVT1: 0.756±0.051; P<0.0001). The Ca 2+ transient duration (CTD100) was longer in PKP2 and RYR2 iPSC-CMs compared to WT before (WT: 1.01±0.05 s, PKP2-1: 1.84±0.01 s, PKP2-2: 1.76±0.02 s, CPVT1: 1.81±0.02 s; P<0.0001) and during ISO (WT: 1.38±0.05 s, PKP2-1: 1.65±0.03 s, PKP2-2: 1.71±0.03 s, CPVT1: 1.61±0.05 s; P<0.001). Before (WT: 259±13 ms, PKP2-1: 538±23 ms, PKP2-2: 493±28 ms, CPVT1: 586±24 ms; P<0.0001) and during ISO (WT: 311±19 ms, PKP2-1: 406±21 ms, P=0.0172, PKP2-2: 487±28 ms, P<0.0001, CPVT1: 453±21 ms, P=0.0001), peak to 50% decay time was slower in PKP2 and RYR2 iPSC-CMs compared with WT. Upstroke time was longer in PKP2 and RYR2 iPSC-CMs compared to WT before (WT: 205±5 ms, PKP2-1: 539±13 ms, PKP2-2: 429±19 ms, CPVT1: 455±12 ms; P<0.0001) and during ISO (WT: 213±7 ms, PKP2-1: 375±16 ms, PKP2-2: 416±20 ms, CPVT1: 389±10 ms; P<0.0001). Conclusion: Here, iPSC-CMs, derived from patients with either PKP2 -mediated ARVC or RYR2 -mediated CPVT, display similar abnormal calcium handling properties such as greater amplitude, longer CTD100, and slower peak to 50% decay time and upstroke time compared to WT iPSC-CMs before and during ISO treatment. This may explain why patients with PKP2 -mediated ARVC often mimic the treadmill stress test seen in patients with CPVT1.

Background: Adults with cardiovascular co-morbidities and risk factors are at greater risk of severe COVID-19. These same risk factors may also be associated with an attenuated antibody response to COVID-19 vaccines, although studies in diverse, U.S. population-based cohorts have been limited. Methods: The Collaborative Cohort of Cohorts for COVID-19 Research (C4R) conducted a serosurvey for SARS-CoV-2 antibodies via dried blood spot (DBS) in 14 U.S. cohorts. IgG antibodies to SARS-CoV-2 spike subunit 1 (S1) and nucleocapsid (N) were measured from DBS using a semi-quantitative microsphere immunoassay and reported as median fluorescence intensity (MFI). Multivariable adjusted linear models regressed log-transformed anti-S1 MFI on age, sex, race/ethnicity, education attainment, self-reported diabetes, hypertension, cardiovascular disease (CVD), chronic kidney disease, smoking history, body mass index (BMI), asthma, obstructive lung diseases, DBS batch, anti-N MFI, vaccine type, time between vaccine and DBS, and vaccine dose at time of DBS collection. Results are presented as the percent difference in anti-S1 MFI compared with a reference group. Results: There were 6614 vaccinated participants prior to booster regimens and DBS collection (April 2021-July 2022) with 50%, 48%, and 2% of the cohort who received BNT162b2, mRNA-1273, or other vaccines, respectively. The mean (SD) time between vaccination and DBS was 3.8 (1.8) months. Over 10% of the cohort had self-reported a history of diabetes, 55% had hypertension, and 74% had a BMI>25 kg/m 2 . Anti-S1 MFI decreased as the time between vaccine dose and DBS collection increased. Diabetes was associated with a 16.1% lower anti-S1 MFI (95%CI:-22.4,-9.5) whereas neither hypertension (-3.8%;95%CI:-9.3,2.1), nor cardiovascular disease history (-5.3%;95%CI:-16.3,7.4) were associated with anti-S1 MFI. Former and current smoking history were each associated with a lower anti-S1 MFI: (-6.6%;95%CI:-12.1,-0.8) and (-16.1%;95%CI:-24.7,-6.6), respectively. Participants with a BMI 25-29.9 kg/m 2 had a 7.6% higher anti-S1 MFI (95%CI:0.3,15.4) whereas those with a BMI of 30-35 kg/m 2 and >35 kg/m 2 had 6.2% (95%CI:-2.4,15.5) higher and 8.9% lower (95%CI:-17.6,0.7) MFI levels, respectively. Older age and male sex were each associated with a lower anti-S1 MFI and mRNA-1273 vaccine, Asian subgroup, higher anti-N titer, and prior COVID-19 infection were each associated with higher anti-S1 MFI. Chronic kidney disease, education attainment, and lung disease were not associated with anti-S1 MFI. Conclusions: Several traditional cardiovascular disease risk factors were associated with diminished humoral responses to the initial COVID-19 vaccine regimens in a diverse U.S. population-based cohort and may have implications on strategies to improve vaccine responses.