To summarize the current understanding of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) throughout the rheumatoid arthritis (RA) disease course from preclinical to established ...disease.
ILD is a serious extra-articular manifestation of RA. Multiple studies have demonstrated a high prevalence of both subclinical and clinical ILD throughout the RA disease course. Investigations of patients without RA have demonstrated an association between RA-related autoantibodies like anticitrullinated protein antibodies (ACPA) and interstitial abnormalities on lung imaging. A significant proportion of RA-ILD patients develop ILD prior to articular manifestations, suggesting that the lung plays a central role in RA development, perhaps through ACPA production. RA-ILD also occurs in early RA, when exuberant autoantibody production and systemic inflammation may propagate pulmonary disease activity. In patients with established RA, a high burden of subclinical and clinical ILD results in significant morbidity, mortality, and healthcare expenditure. Multiple epidemiologic and genetic risk factors, as well as serum biomarkers, have been associated with RA-ILD.
Subclinical and clinical ILD occur frequently in preclinical, early, and established RA and may play a key role in RA-related autoantibody production and disease progression. Further studies are needed to better understand the risk factors, prognosis, and potential therapies for RA-ILD.
Objective
Patients with axial spondyloarthritis (axSpA) often experience significant delay between symptom onset and diagnosis for reasons that are incompletely understood. We investigated ...associations between demographic, medical, and socioeconomic factors and axSpA diagnostic delay.
Methods
We identified patients meeting modified New York criteria for ankylosing spondylitis (AS) or 2009 Assessment of Spondyloarthritis International Society criteria for axSpA in the Mass General Brigham health care system between December 1990 and October 2021. We determined the duration of diagnostic delay, defined as the duration of back pain symptoms reported at diagnosis, as well as disease manifestations and specialty care prior to diagnosis from the electronic health record. We obtained each patient's Social Vulnerability Index (SVI) by mapping their address to the US Centers for Disease Control SVI Atlas. We examined associations among disease manifestations, SVI, and diagnostic delay using ordinal logistic regression.
Results
Among 554 patients with axSpA who had a median diagnostic delay of 3.8 years (interquartile range 1.1–10), peripheral arthritis (odds ratio OR 0.65, 95% confidence interval CI 0.45–0.93) and older age at symptom onset (OR 0.83, 95% CI 0.78–0.88 per five years) were associated with shorter delay. AS at diagnosis (OR 1.85, 95% CI 1.30–2.63), a history of uveitis prior to diagnosis (OR 2.77, 95% CI 1.73–4.52), and higher social vulnerability (defined as national SVI 80th to 99th percentiles; OR 1.99, 95% CI 1.06–3.84) were associated with longer diagnostic delay.
Conclusion
Older age at back pain onset and peripheral arthritis were associated with shorter delay, whereas uveitis was associated with longer diagnostic delay. Patients with higher socioeconomic vulnerability had longer diagnostic delay independent of clinical factors.
Colorectal cancer is the second leading cause of cancer death in the United States, with over 50,000 deaths estimated in 2014. Molecular profiling for somatic mutations that predict absence of ...response to anti-EGFR therapy has become standard practice in the treatment of metastatic colorectal cancer; however, the quantity and type of tissue available for testing is frequently limited. Further, the degree to which the primary tumor is a faithful representation of metastatic disease has been questioned. As next-generation sequencing technology becomes more widely available for clinical use and additional molecularly targeted agents are considered as treatment options in colorectal cancer, it is important to characterize the extent of tumor heterogeneity between primary and metastatic tumors.
We performed deep coverage, targeted next-generation sequencing of 230 key cancer-associated genes for 69 matched primary and metastatic tumors and normal tissue. Mutation profiles were 100% concordant for KRAS, NRAS, and BRAF, and were highly concordant for recurrent alterations in colorectal cancer. Additionally, whole genome sequencing of four patient trios did not reveal any additional site-specific targetable alterations.
Colorectal cancer primary tumors and metastases exhibit high genomic concordance. As current clinical practices in colorectal cancer revolve around KRAS, NRAS, and BRAF mutation status, diagnostic sequencing of either primary or metastatic tissue as available is acceptable for most patients. Additionally, consistency between targeted sequencing and whole genome sequencing results suggests that targeted sequencing may be a suitable strategy for clinical diagnostic applications.
Dilated cardiomyopathy is characterized by substantial locus, allelic, and clinical heterogeneity that necessitates testing of many genes across clinically overlapping diseases. Few studies have ...sequenced sufficient individuals; thus, the contributions of individual genes and the pathogenic variant spectrum are still poorly defined. We analyzed 766 dilated cardiomyopathy patients tested over 5 years in our molecular diagnostics laboratory.
Patients were tested using gene panels of increasing size from 5 to 46 genes, including 121 cases tested with a multiple-cardiomyopathy next-generation panel covering 46 genes. All variants were reassessed using our current clinical-grade scoring system to eliminate false-positive disease associations that afflict many older analyses.
Up to 37% of dilated cardiomyopathy cases carry a clinically relevant variant in one of 20 genes, titin (TTN) being the largest contributor (up to 14%). Desmoplakin (DSP), an arrhythmogenic right ventricular cardiomyopathy gene, contributed 2.4%, illustrating the utility of multidisease testing. The clinical sensitivity increased from 10 to 37% as gene panel sizes increased. However, the number of inconclusive cases also increased from 4.6 to 51%.
Our data illustrate the utility of broad gene panels for genetically and clinically heterogeneous diseases but also highlight challenges as molecular diagnostics moves toward genome-wide testing.
Abstract
Objective
To investigate the prevalence and mortality impact of interstitial lung abnormalities (ILAs) in RA and non-RA comparators.
Methods
We analysed associations between ILAs, RA, and ...mortality in COPDGene, a multicentre prospective cohort study of current and past smokers, excluding known interstitial lung disease (ILD) or bronchiectasis. All participants had research chest high-resolution CT (HRCT) reviewed by a sequential reading method to classify ILA as present, indeterminate or absent. RA cases were identified by self-report RA and DMARD use; non-RA comparators had neither an RA diagnosis nor used DMARDs. We examined the association and mortality risk of RA and ILA using multivariable logistic regression and Cox regression.
Results
We identified 83 RA cases and 8725 non-RA comparators with HRCT performed for research purposes. ILA prevalence was 16.9% in RA cases and 5.0% in non-RA comparators. After adjusting for potential confounders, including genetics, current/past smoking and other lifestyle factors, ILAs were more common among those with RA compared with non-RA odds ratio 4.76 (95% CI 2.54, 8.92). RA with ILAs or indeterminate for ILAs was associated with higher all-cause mortality compared with non-RA without ILAs hazard ratio (HR) 3.16 (95% CI 2.11, 4.74) and RA cases without ILA HR 3.02 (95% CI 1.36, 6.75).
Conclusions
In this cohort of smokers, RA was associated with ILAs and this persisted after adjustment for current/past smoking and genetic/lifestyle risk factors. RA with ILAs in smokers had a 3-fold increased all-cause mortality, emphasizing the importance of further screening and treatment strategies for preclinical ILD in RA.
There have been limited investigations of the prevalence and mortality impact of quantitative computed tomography (QCT) parenchymal lung features in rheumatoid arthritis (RA). We examined the ...cross-sectional prevalence and mortality associations of QCT features, comparing RA and non-RA participants.
We identified participants with and without RA in COPDGene, a multicentre cohort study of current or former smokers. Using a k-nearest neighbor quantifier, high resolution CT chest scans were scored for percentage of normal lung, interstitial changes, and emphysema. We examined associations between QCT features and RA using multivariable linear regression. After dichotomizing participants at the 75th percentile for each QCT feature among non-RA participants, we investigated mortality associations by RA/non-RA status and quartile 4 vs quartiles 1-3 of QCT features using Cox regression. We assessed for statistical interactions between RA and QCT features.
We identified 82 RA cases and 8820 non-RA comparators. In multivariable linear regression, RA was associated with higher percentage of interstitial changes (β = 1.7 ± 0.5, p= 0.0008) but not emphysema (β = 1.3 ± 1.7, p= 0.44). Participants with RA and >75th percentile of emphysema had significantly higher mortality than non-RA participants (HR 5.86, 95%CI 3.75-9.13) as well as RA participants (HR 5.56, 95%CI 2.71-11.38) with ≤75th percentile of emphysema. There were statistical interactions between RA and emphysema for mortality (multiplicative p= 0.014; attributable proportion 0.53, 95%CI 0.30-0.70).
Using machine learning-derived QCT data in a cohort of smokers, RA was associated with higher percentage of interstitial changes. The combination of RA and emphysema conferred >5-fold higher mortality.
Our aim was to investigate the effectiveness and tolerability of antifibrotics in a real-world cohort of patients with rheumatoid arthritis-associated interstitial lung diseases (RA-ILD).
In this ...retrospective cohort study, we identified RA-ILD patients initiating antifibrotics at Mass General Brigham Integrated Health Care System, a large multi-hospital healthcare system in Boston, MA, USA. We used electronic query to identify all patients with at least 2 RA diagnosis codes and a prescription for either nintedanib or pirfenidone (2014-2023). All analyzed patients met 2010 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for RA and had definite RA-ILD according to Bongartz criteria. Data regarding pulmonary function test (PFT) results, adverse events (AEs), tolerability, and clinical data were collected. A linear mixed model with random intercept was used to compare the within-patient trajectory of the percent predicted forced vital capacity (FVCpp) within 18-months before to 18-months after antifibrotic initiation among those with these PFT data. Lung transplant-free survival and drug retention was estimated in a Kaplan-Meier analysis and a Cox regression analysis was performed to identify independent baseline factors associated with lung transplant or mortality.
We analyzed 74 patients with RA-ILD that initiated antifibrotics (mean age 67.8 years, 53 % male); 40 patients initiated nintedanib and 34 initiated pirfenidone. Median follow-up was 89 weeks (min 4, max 387). There was a significant improvement in the estimated slope of FVCpp after antifibrotic initiation (-0.3 % per year after initiation compared to -6.2 % per year before antifibrotic initiation, p = 0.03). Nintedanib and pirfenidone had similar FVCpp trajectory. Twenty-six patients (35 %) died and 4 (5 %) had undergone lung transplantation during follow-up. Male sex and heavy smoking were each associated with the composite outcome of lung transplant or mortality. AEs were reported in 41 (55 %) patients, with gastrointestinal (GI) AEs being most common (n = 30). The initial antifibrotic was discontinued in 34 (46 %) patients mostly due to GI AEs (n = 19). The median drug retention time was 142 weeks (95 %CI 56, 262) with no difference between nintedanib and pirfenidone (p = 0.68).
In this first real-world study of antifibrotic use dedicated to RA-ILD, antifibrotic initiation was associated with a modestly improved trajectory of FVCpp. AEs were frequently reported, particularly GI, and discontinuation was common. However, lung transplant and mortality rates were still high, emphasizing the need for further therapeutic strategies in patients with severe RA-ILD. These real-world data complement previous trial data that investigated efficacy and safety.
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