Updating and Validating the Rheumatic Disease Comorbidity Index to ICD-10-CM

Background/Objective: Comorbidities can contribute to increased risk for mortality and disability in individuals with rheumatoid arthritis (RA)1,2. The Rheumatic Disease Comorbidity Index (RDCI) assesses 11 comorbidities and produces a weighted score (0-9) that accurately predicts several health outcomes3. The RDCI was developed with self-report data and later validated with ICD-9-CM codes collected from administrative data3,4. On October 1, 2015, the U.S. transitioned to ICD-10-CM, resulting in a nearly five-fold increase in the number of codes available to classify conditions5. Our objective was to update the RDCI by translating it into ICD-10-CM. Methods: We defined an ICD-9-CM cohort and an ICD-10-CM cohort using patient data from the Veterans Affairs Rheumatoid Arthritis Registry (VARA). ICD-10-CM codes were generated by converting ICD-9-CM codes using tools that provide suggested crosswalks, and the codes were reviewed by a physician to assess clinical relevance. Comorbidities were collected from national VA administrative data over a two-year period in both cohorts (ICD-9-CM: October 1, 2013 to September 30, 2015; ICD-10-CM: January 1, 2016 to December 31, 2017). Comorbidity frequencies were compared using Cohen’s Kappa, and RDCI scores were compared using Intraclass Correlation Coefficients (ICC). Results: Both the ICD-9-CM cohort (n=1,082) and ICD-10-CM cohort (n=1,446) were predominantly male (ICD-9-CM: 89%; ICD-10-CM: 87%), Caucasian (ICD-9-CM: 76%; ICD-10-CM: 73%), and middle to old-aged (ICD-9-CM: 67.3 ± 10.2 years; ICD-10-CM: 68.2 ± 10.0 years). Prevalence of comorbidities were similar between coding systems, with absolute differences less than 4% (range: 0.28 to 3.91). Myocardial infarction, hypertension, diabetes mellitus, depression, stroke, other cardiovascular, lung disease, and cancer had moderate agreement or higher (range κ: 0.47 to 0.84), while fracture and ulcer/stomach problem had slight and fair agreement, respectively (κ = 0.13; κ = 0.27)6,7. The RDCI scores were 2.95 ± 1.73 (mean ± SD) for the ICD-9-CM cohort and 2.93 ± 1.75 for the ICD-10-CM cohort. RDCI scores had moderate agreement (ICC: 0.71; 95% CI: 0.68-0.74)8 among individuals who were observed during both the ICD-9-CM and ICD-10-CM eras. Conclusion: We have mapped the RDCI from ICD-9-CM to ICD-10-CM codes, generating comparable RDCI scores in a large RA registry. Individual comorbidity agreement varied, with more chronic conditions such as diabetes and hypertension having higher agreement and more acute conditions such as fractures and ulcer/stomach problems having lower agreement. The updated RDCI can be used in clinical outcomes research with ICD-10-CM era patient data.https://digitalcommons.unmc.edu/surp2021/1043/thumbnail.jp

Citrullinated and Malondialdehyde-Acetaldehyde Modified Fibrinogen Activates Macrophages and Promotes an Aggressive Synovial Fibroblast Phenotype in Patients with Rheumatoid Arthritis

Objective: Post-translational protein modifications with malondialdehyde-acetaldehyde (MAA) and citrulline (CIT) are implicated in the pathogenesis of rheumatoidarthritis (RA). Although precise mechanisms have not been elucidated, macrophage-fibroblast interactions have been proposed to play a central role in the development and progression of RA. The purpose of our study was to evaluate the downstream effects of macrophage released soluble mediators, following stimulation with fibrinogen (FIB) modified antigens, on human fibroblast-like synoviocytes (HFLS). Methods: PMA-treated U-937 monocytes (Mϕ) and macrophage-differentiated peripheral blood mononuclear cells (MP) were stimulated with FIB, FIB-MAA, FIB-CIT, or FIB-MAA-CIT. HFLS-RA cells were stimulated directly with FIB antigens or with supernatants (SN) from macrophages (Mϕ-SN or MP-SN) stimulated with FIB antigens. Genes associated with an aggressive HFLS phenotype, extracellular matrix proteins, and activated signaling pathways were evaluated. Results: HFLS-RA cells treated with Mϕ-SNFIB-CIT and Mϕ-SNFIB-MAA-CIT demonstrated significant increases in mRNA expression of genes associated with an aggressive phenotype at 24-h as compared to direct stimulation with the same antigens. Similar results were obtained using MP-SN. Cellular morphology was altered and protein expression of vimentin (p\u3c0.0001 vs. Mϕ-SNFIB) and type II collagen (p\u3c0.0001) were significantly increased in HFLS-RA cells treated with any of the Mϕ-SN generated following stimulation with modified antigens. Phosphorylation of JNK, Erk1/2, and Akt were increased most substantially in HFLS-RA treated with Mϕ-SNFIB-MAA-CIT (p\u3c0.05 vs Mϕ-SNFIB). These and other data suggested the presence of PDGF-BB in Mϕ-SN. Mϕ-SNFIB-MAA-CIT contained the highest concentration of PDGF-BB (p\u3c0.0001 vs. Mϕ-SNFIB) followed by Mϕ-SNFIB-CIT then Mϕ-SNFIB-MAA. HFLS-RA cells treated with PDGF-BB showed similar cellular morphology to the Mϕ-SN generated following stimulation with modified FIB, as well as the increased expression of vimentin, type II collagen, and the phosphorylation of JNK, Erk1/2 and Akt signaling molecules. Conclusion: Together, these findings support the hypothesis that in response to MAA-modified and/or citrullinated fibrinogen,macrophages release soluble factors including PDGF-BB that induce fibroblast activation and promote an aggressive fibroblast phenotype. These cellular responses were most robust following macrophage activation with dually modified fibrinogen, compared to single modification alone, providing novel insights into the combined role of multiple post-translational protein modifications in the development of RA

The Induction of Autoimmune Arthritis and Sex differences in Mice Impact the Lung Inflammatory Response to Repetitive Inhalant Organic Dust Extract Exposures

Asthma, chronic bronchitis and COPD are common adverse respiratory health effects among persons exposed to agriculture organic dust work environments. Occupational inhalant exposures have been increasingly associated with the risk of rheumatoid arthritis (RA) disease development, particularly among males. Agriculture workers have increased risk of RA and generalized bone disease. Chronic lung disease is associated with production of characteristic autoantibodies associated with RA (e.g.anti-citrullinated antibodies), even in absence of RA disease. The mechanistic link between pulmonary inflammation and arthritis (and vice versa) remains poorly understood. Animal models are lacking.https://digitalcommons.unmc.edu/emet_posters/1004/thumbnail.jp

Citrullinated and malondialdehyde-acetaldehyde modified fibrinogen activates macrophages and promotes an aggressive synovial fibroblast phenotype in patients with rheumatoid arthritis

ObjectivePost-translational protein modifications with malondialdehyde-acetaldehyde (MAA) and citrulline (CIT) are implicated in the pathogenesis of rheumatoid arthritis (RA). Although precise mechanisms have not been elucidated, macrophage-fibroblast interactions have been proposed to play a central role in the development and progression of RA. The purpose of our study was to evaluate the downstream effects of macrophage released soluble mediators, following stimulation with fibrinogen (FIB) modified antigens, on human fibroblast-like synoviocytes (HFLS).MethodsPMA-treated U-937 monocytes (Mϕ) and macrophage-differentiated peripheral blood mononuclear cells (MP) were stimulated with FIB, FIB-MAA, FIB-CIT, or FIB-MAA-CIT. HFLS-RA cells were stimulated directly with FIB antigens or with supernatants (SN) from macrophages (Mϕ-SN or MP-SN) stimulated with FIB antigens. Genes associated with an aggressive HFLS phenotype, extracellular matrix proteins, and activated signaling pathways were evaluated.ResultsHFLS-RA cells treated with Mϕ-SNFIB-CIT and Mϕ-SNFIB-MAA-CIT demonstrated significant increases in mRNA expression of genes associated with an aggressive phenotype at 24-h as compared to direct stimulation with the same antigens. Similar results were obtained using MP-SN. Cellular morphology was altered and protein expression of vimentin (p<0.0001 vs. Mϕ-SNFIB) and type II collagen (p<0.0001) were significantly increased in HFLS-RA cells treated with any of the Mϕ-SN generated following stimulation with modified antigens. Phosphorylation of JNK, Erk1/2, and Akt were increased most substantially in HFLS-RA treated with Mϕ-SNFIB-MAA-CIT (p<0.05 vs Mϕ-SNFIB). These and other data suggested the presence of PDGF-BB in Mϕ-SN. Mϕ-SNFIB-MAA-CIT contained the highest concentration of PDGF-BB (p<0.0001 vs. Mϕ-SNFIB) followed by Mϕ-SNFIB-CIT then Mϕ-SNFIB-MAA. HFLS-RA cells treated with PDGF-BB showed similar cellular morphology to the Mϕ-SN generated following stimulation with modified FIB, as well as the increased expression of vimentin, type II collagen, and the phosphorylation of JNK, Erk1/2 and Akt signaling molecules.ConclusionTogether, these findings support the hypothesis that in response to MAA-modified and/or citrullinated fibrinogen, macrophages release soluble factors including PDGF-BB that induce fibroblast activation and promote an aggressive fibroblast phenotype. These cellular responses were most robust following macrophage activation with dually modified fibrinogen, compared to single modification alone, providing novel insights into the combined role of multiple post-translational protein modifications in the development of RA

High-Throughput Analysis of Lung Immune Cells in a Combined Murine Model of Agriculture Dust-Triggered Airway Inflammation With Rheumatoid Arthritis

Rheumatoid arthritis (RA)-associated lung disease is a leading cause of mortality in RA, yet the mechanisms linking lung disease and RA remain unknown. Using an established murine model of RA-associated lung disease combining collagen-induced arthritis (CIA) with organic dust extract (ODE)-induced airway inflammation, differences among lung immune cell populations were analyzed by single cell RNA-sequencing. Additionally, four lung myeloid-derived immune cell populations including macrophages, monocytes/macrophages, monocytes, and neutrophils were isolated by fluorescence cell sorting and gene expression was determined by NanoString analysis. Unsupervised clustering revealed 14 discrete clusters among Sham, CIA, ODE, and CIA+ODE treatment groups: 3 neutrophils (inflammatory, resident/transitional, autoreactive/suppressor), 5 macrophages (airspace, differentiating/recruited, recruited, resident/interstitial, and proliferative airspace), 2 T-cells (differentiating and effector), and a single cluster each of inflammatory monocytes, dendritic cells, B-cells and natural killer cells. Inflammatory monocytes, autoreactive/suppressor neutrophils, and recruited/differentiating macrophages were predominant with arthritis induction (CIA and CIA+ODE). By specific lung cell isolation, several interferon-related and autoimmune genes were disproportionately expressed among CIA and CIA+ODE (e.g. Oasl1, Oas2, Ifit3, Gbp2, Ifi44, and Zbp1), corresponding to RA and RA-associated lung disease. Monocytic myeloid-derived suppressor cells were reduced, while complement genes (e.g. C1s1 and Cfb) were uniquely increased in CIA+ODE mice across cell populations. Recruited and inflammatory macrophages/monocytes and neutrophils expressing interferon-, autoimmune-, and complement-related genes might contribute towards pro-fibrotic inflammatory lung responses following airborne biohazard exposures in setting of autoimmune arthritis and could be predictive and/or targeted to reduce disease burden