Replicating prediction algorithms for hospitalization and corticosteroid use in patients with inflammatory bowel disease.

INTRODUCTION: Previous work had shown that machine learning models can predict inflammatory bowel disease (IBD)-related hospitalizations and outpatient corticosteroid use based on patient demographic and laboratory data in a cohort of United States Veterans. This study aimed to replicate this modeling framework in a nationally representative cohort. METHODS: A retrospective cohort design using Optum Electronic Health Records (EHR) were used to identify IBD patients, with at least 12 months of follow-up between 2007 and 2018. IBD flare was defined as an inpatient/emergency visit with a diagnosis of IBD or an outpatient corticosteroid prescription for IBD. Predictors included demographic and laboratory data. Logistic regression and random forest (RF) models were used to predict IBD flare within 6 months of each visit. A 70% training and 30% validation approach was used. RESULTS: A total of 95,878 patients across 780,559 visits were identified. Of these, 22,245 (23.2%) patients had at least one IBD flare. Patients were predominantly White (87.7%) and female (57.1%), with a mean age of 48.0 years. The logistic regression model had an area under the receiver operating curve (AuROC) of 0.66 (95% CI: 0.65-0.66), sensitivity of 0.69 (95% CI: 0.68-0.70), and specificity of 0.74 (95% CI: 0.73-0.74) in the validation cohort. The RF model had an AuROC of 0.80 (95% CI: 0.80-0.81), sensitivity of 0.74 (95% CI: 0.73-0.74), and specificity of 0.72 (95% CI: 0.72-0.72) in the validation cohort. Important predictors of IBD flare in the RF model were the number of previous flares, age, potassium, and white blood cell count. CONCLUSION: The machine learning modeling framework was replicated and results showed a similar predictive accuracy in a nationally representative cohort of IBD patients. This modeling framework could be embedded in routine practice as a tool to distinguish high-risk patients for disease activity.

Differential Cardiopulmonary Health Impacts of Local and Long-Range Transport of Wildfire Smoke.

We estimated cardiopulmonary morbidity and mortality associated with wildfire smoke (WFS) fine particulate matter (PM2.5) in the Front Range of Colorado from 2010 to 2015. To estimate WFS PM2.5, we developed a daily kriged PM2.5 surface at a 15  × 15 km resolution based on the Environmental Protection Agency Air Quality System monitors for the western United States; we subtracted out local seasonal-average PM2.5 of nonsmoky days, identified using satellite-based smoke plume estimates, from the local daily estimated PM2.5 if smoke was identified by National Oceanic and Atmospheric Administration's Hazard Mapping System. We implemented time-stratified case-crossover analyses to estimate the effect of a 10 µg/m3 increase in WFS PM2.5 with cardiopulmonary hospitalizations and deaths using single and distributed lag models for lags 0-5 and distinct annual impacts based on local and long-range smoke during 2012, and long-range transport of smoke in 2015. A 10 µg/m3 increase in WFS was associated with all respiratory, asthma, and chronic obstructive pulmonary disease hospitalizations for lag day 3 and hospitalizations for ischemic heart disease at lag days 2 and 3. Cardiac arrest deaths were associated with WFS PM2.5 at lag day 0. For 2012 local wildfires, asthma hospitalizations had an inverse association with WFS PM2.5 (OR: 0.716, 95% CI: 0.517-0.993), but a positive association with WFS PM2.5 during the 2015 long-range transport event (OR: 1.455, 95% CI: 1.093-1.939). Cardiovascular mortality was associated with the 2012 long-range transport event (OR: 1.478, 95% CI: 1.124-1.944).

The association between wildfire smoke exposure and asthma-specific medical care utilization in Oregon during the 2013 wildfire season.

Wildfire smoke (WFS) increases the risk of respiratory hospitalizations. We evaluated the association between WFS and asthma healthcare utilization (AHCU) during the 2013 wildfire season in Oregon. WFS particulate matter ≤ 2.5 µm in diameter (PM2.5) was estimated using a blended model of in situ monitoring, chemical transport models, and satellite-based data. Asthma claims and place of service were identified from Oregon All Payer All Claims data from 1 May 2013 to 30 September 2013. The association with WFS PM2.5 was evaluated using time-stratified case-crossover designs. The maximum WFS PM2.5 concentration during the study period was 172 µg/m3. A 10 µg/m3 increase in WFS increased risk in asthma diagnosis at emergency departments (odds ratio [OR]: 1.089, 95% confidence interval [CI]: 1.043-1.136), office visit (OR: 1.050, 95% CI: 1.038-1.063), and outpatient visits (OR: 1.065, 95% CI: 1.029-1.103); an association was observed with asthma rescue inhaler medication fills (OR: 1.077, 95% CI: 1.065-1.088). WFS increased the risk for asthma morbidity during the 2013 wildfire season in Oregon. Communities impacted by WFS could see increases in AHCU for tertiary, secondary, and primary care.

A national burden assessment of estimated pediatric asthma emergency department visits that may be attributed to elevated ozone levels associated with the presence of smoke.

Asthma is the most common pediatric disease in the USA. It has been consistently demonstrated that asthma symptoms are exacerbated by exposure to ozone. Ozone (O3) is a secondary pollutant produced when volatile organic compounds (VOCs) are oxidized in the atmosphere in the presence of nitrogen oxides (NOx). At ground level, elevated ozone is typically formed as a result of human activities. However, wildfires represent an additional source of ozone precursors. Recent evidence suggests that smoke can increase ozone concentrations. We estimated the number of excess asthma-related emergency department (ED) visits in children with asthma that may be attributed to elevated ozone associated with smoke (EOAS) in the USA. We conducted a quantitative burden assessment (BA) using a Monte Carlo approach to estimate the median number of excess pediatric asthma ED visits that may be attributed to EOAS among children with asthma in the continental USA between 2005 and 2014, as well as 95% confidence bounds (95% CB). We estimated that a median of 2403 (95% CB 235-5382) pediatric asthma ED visits could be attributed to EOAS exposure between 2005 and 2014 in the continental USA. Furthermore, the impact of EOAS on estimated asthma ED visits was greatest in the eastern half of the continental USA. We found a significant increase in pediatric asthma ED visits that may be attributed to exposure to EOAS. EOAS may have a measurable negative impact on children with asthma in the USA.

Triple Positivity for Anti-Citrullinated Protein Autoantibodies, Rheumatoid Factor, and Anti-Carbamylated Protein Antibodies Conferring High Specificity for Rheumatoid Arthritis: Implications for Very Early Identification of At-Risk Individuals.

OBJECTIVE: In rheumatoid arthritis (RA), anti-citrullinated protein antibodies (ACPAs) and rheumatoid factor (RF) are commonly used to aid in the diagnosis. Although these autoantibodies are mainly found in RA, their specificity is not optimal. It is therefore difficult to identify RA patients, especially in very early disease, based on the presence of ACPAs and RF alone. In addition, anti-carbamylated protein (anti-CarP) antibodies have diagnostic and prognostic value, since their presence is associated with joint damage in RA patients and also associated with the future development of RA in patients with arthralgia. Therefore, the aim of the present study was to investigate the value of combined antibody testing in relation to prediction and diagnosis of (early) RA. METHODS: A literature search resulted in identification of 12 relevant studies, consisting of RA patients, pre-RA individuals, disease controls, healthy first-degree relatives of RA patients, and healthy control subjects, in which data on RF, ACPAs, and anti-CarP antibody status were available. Using these data, random effects meta-analyses were carried out for several antibody combinations. RESULTS: The individual antibodies were highly prevalent in patients with RA (34-80%) compared to the control groups, but were also present in non-RA controls (0-23%). For the classification of most subjects correctly as having RA or as a non-RA control, the combination of ACPAs and/or RF often performed well (specificity 65-100%, sensitivity 59-88%). However, triple positivity for ACPAs, RF, and anti-CarP antibodies resulted in a higher specificity for RA (98-100%), accompanied by a lower sensitivity (11-39%). CONCLUSION: As the rheumatology field is moving toward very early identification of RA and possible screening for individuals at maximum risk of RA in populations with a low pretest probability, an autoantibody profile of triple positivity for ACPAs, RF, and anti-CarP provides interesting information that might help identify individuals at risk of developing RA.

Association of Antibodies to Citrullinated Protein Antigens with Blood Pressure in First-Degree Relatives of Rheumatoid Arthritis Patients: The Studies of the Etiology of Rheumatoid Arthritis.

BACKGROUND: Hypertension is more common in patients with rheumatoid arthritis (RA) than in the general population. It is unknown whether hypertension is due to RA-related medications or the disease itself. Therefore, we sought to investigate associations between RA-related autoantibodies, specifically antibodies to citrullinated protein antigens (ACPA) and systolic blood pressure (SBP) and diastolic blood pressure (DBP) in first-degree relatives of RA patients, who were free of RA and RA-related medications. We hypothesized that a greater number of detectable ACPA would be associated with high SBP and DBP, independent of other risk factors in these first-degree relatives. METHODS: We evaluated associations between ACPA and SBP and DBP in a cross-sectional study of 72 first-degree relatives (defined as parent, child, or sibling) of RA patients. Fifteen ACPA were measured using a Bio-Plex bead-based assay; each was dichotomized as positive/negative based on pre-specified cut-points. Analysis of covariance was used to evaluate associations between ACPA positivity and SBP and DBP, adjusting for age, sex, race, body mass index (BMI), pack-years of smoking, high sensitivity C-reactive protein (hsCRP), and current use of anti-hypertensive medications. RESULTS: Average age was 51 and 69% were women. Mean SBP was 119 ± 18 and DBP was 74 ± 9 mm Hg. Thirty-three (46%) first-degree relatives were positive for ≥1 ACPA; and were younger, had lower BMI, more pack-years of smoking, and higher hsCRP concentrations compared to ACPA negative first-degree relatives. For each additional positive ACPA, SBP was 0.98 ± 0.5 mm Hg (p = 0.05) higher, and DBP was 0.66 ± 0.3 mm Hg (p = 0.04) higher. Anti-cit-fibrinogen A (211-230) positive and anti-cit-filaggrin positive first-degree relatives had 11.5 and 13.9 mm Hg higher SBP (p = 0.02) respectively. Anti-cit-clusterin, cit-filaggrin, and cit-vimentin positive first-degree relatives had 7-8 mm Hg higher DBP (p = 0.03, 0.05, 0.05 respectively), compared to being negative for these individual ACPA. Consistent with associations between ACPA, SBP, and DBP, anti-cyclic citrullinated peptides (anti-CCP2) positive first-degree relatives had 16.4± (p = 0.03) higher SBP and 12.1± mm Hg (p = 0.01) higher DBP than anti-CCP2 negative first-degree relatives. CONCLUSION: In first-degree relatives without RA, ACPA positivity is associated with higher SBP and DBP. Subclinical autoimmune processes and ACPA may play a role in the vascular changes potentially leading to hypertension prior to RA onset.

The association between omega-3 fatty acid biomarkers and inflammatory arthritis in an anti-citrullinated protein antibody positive population.

Objectives: Higher circulating omega-3 fatty acids (n-3 FAs) are associated with a lower prevalence of anti-CCP antibodies and RF in subjects without RA. We examined whether, in anti-CCP+ subjects, n-3 FAs also play a role in development of inflammatory arthritis (IA). Methods: At Colorado-based health fairs from 2008 to 2014, participants without a previous diagnosis of RA who were anti-CCP3+ (n = 47) were recruited into a follow-up study; symptom assessments and joint examinations were conducted every 6 months for the determination of IA. We measured n-3 FAs as a percentage of total lipids in red blood cell membranes (n-3 FA%) at each visit. Results: We detected IA in 10 anti-CCP3+ subjects (21%) at the baseline visit. Increased total n-3 FA% in red blood cell membranes [odds ratio (OR) = 0.09, 95% CI: 0.01, 0.76], specifically docosapentaenoic acid (OR = 0.16, 95% CI: 0.03, 0.83) and docosahexaenoic acid (OR = 0.23, 95% CI: 0.06, 0.86), was associated with a lower odds of IA at the baseline visit, adjusting for n-3 FA supplement use, current smoking, RF+, elevated CRP+ and shared epitope. We followed 35 of the anti-CCP3+ subjects who were IA negative at baseline and detected 14 incident IA cases over an average of 2.56 years of follow-up. In a time-varying survival analysis, increasing docosapentaenoic acid significantly decreased risk of incident IA (hazard ratio = 0.52, 95% CI: 0.27, 0.98), adjusting for age at baseline, n-3 FA supplement use, RF+, CRP+ and shared epitope. Conclusion: n-3 FAs may potentially lower the risk of transition from anti-CCP positivity to IA, an observation that warrants further investigation.

Comparison of wildfire smoke estimation methods and associations with cardiopulmonary-related hospital admissions.

Climate forecasts predict an increase in frequency and intensity of wildfires. Associations between health outcomes and population exposure to smoke from Washington 2012 wildfires were compared using surface monitors, chemical-weather models, and a novel method blending three exposure information sources. The association between smoke particulate matter ≤2.5 µm in diameter (PM2.5) and cardiopulmonary hospital admissions occurring in Washington from 1 July to 31 October 2012 was evaluated using a time-stratified case-crossover design. Hospital admissions aggregated by ZIP code were linked with population-weighted daily average concentrations of smoke PM2.5 estimated using three distinct methods: a simulation with the Weather Research and Forecasting with Chemistry (WRF-Chem) model, a kriged interpolation of PM2.5 measurements from surface monitors, and a geographically weighted ridge regression (GWR) that blended inputs from WRF-Chem, satellite observations of aerosol optical depth, and kriged PM2.5. A 10 µg/m3 increase in GWR smoke PM2.5 was associated with an 8% increased risk in asthma-related hospital admissions (odds ratio (OR): 1.076, 95% confidence interval (CI): 1.019-1.136); other smoke estimation methods yielded similar results. However, point estimates for chronic obstructive pulmonary disease (COPD) differed by smoke PM2.5 exposure method: a 10 µg/m3 increase using GWR was significantly associated with increased risk of COPD (OR: 1.084, 95%CI: 1.026-1.145) and not significant using WRF-Chem (OR: 0.986, 95%CI: 0.931-1.045). The magnitude (OR) and uncertainty (95%CI) of associations between smoke PM2.5 and hospital admissions were dependent on estimation method used and outcome evaluated. Choice of smoke exposure estimation method used can impact the overall conclusion of the study.

Spatial and temporal estimates of population exposure to wildfire smoke during the Washington state 2012 wildfire season using blended model, satellite, and in situ data.

In the western U.S., smoke from wild and prescribed fires can severely degrade air quality. Due to changes in climate and land management, wildfires have increased in frequency and severity, and this trend is expected to continue. Consequently, wildfires are expected to become an increasingly important source of air pollutants in the western U.S. Hence, there is a need to develop a quantitative understanding of wildfire-smoke-specific health effects. A necessary step in this process is to determine who was exposed to wildfire smoke, the concentration of the smoke during exposure, and the duration of the exposure. Three different tools have been used in past studies to assess exposure to wildfire smoke: in situ measurements, satellite-based observations, and chemical-transport model (CTM) simulations. Each of these exposure-estimation tools has associated strengths and weakness. We investigate the utility of blending these tools together to produce estimates of PM2.5 exposure from wildfire smoke during the Washington 2012 fire season. For blending, we use a ridge-regression model and a geographically weighted ridge-regression model. We evaluate the performance of the three individual exposure-estimate techniques and the two blended techniques by using leave-one-out cross validation. We find that predictions based on in situ monitors are more accurate for this particular fire season than the CTM simulations and satellite-based observations because of the large number of monitors present; therefore, blending provides only marginal improvements above the in situ observations. However, we show that in hypothetical cases with fewer surface monitors, the two blending techniques can produce substantial improvement over any of the individual tools.

Omega-3 fatty acids are associated with a lower prevalence of autoantibodies in shared epitope-positive subjects at risk for rheumatoid arthritis.

OBJECTIVES: Previously, we found that omega-3 fatty acids (n-3 FAs) were inversely associated with anti-cyclic citrullinated peptide (anti-CCP) positivity in participants at risk for future rheumatoid arthritis (RA). We investigated whether n-3 FAs were also associated with rheumatoid factor (RF) positivity and whether these associations were modified by shared epitope (SE) positivity. METHODS: The Studies of the Etiology of RA (SERA) cohort includes RA-free participants who are at increased risk for RA. We conducted a nested case-control study (n=136) to determine the association between RF and anti-CCP2 positivity and n-3 FA percentage in erythrocyte membranes (n-3 FA% in red blood cells (RBCs)). Additionally, in the baseline visit of the SERA cohort (n=2166), we evaluated the association between reported n-3 FA supplement use and prevalence of RF and anti-CCP2. We assessed SE positivity as an effect modifier. RESULTS: In the case-control study, increasing n-3 FA% in RBCs was inversely associated with RF positivity in SE-positive participants (OR 0.27, 95% CI 0.10 to 0.79), but not SE-negative participants. Similar associations were seen with anti-CCP positivity in SE-positive participants (OR 0.42, 95% CI 0.20 to 0.89), but not SE-negative participants. In the SERA cohort at baseline, n-3 FA supplement use was associated with a lower prevalence of RF positivity in SE-positive participants (OR 0.32, 95% CI 0.12 to 0.82), but not SE-negative participants; similar but non-significant trends were observed with anti-CCP2. CONCLUSIONS: The potential protective effect of n-3 FAs on RA-related autoimmunity may be most pronounced in those who exhibit HLA class II genetic susceptibility to RA.

Associations of Smoking and Age With Inflammatory Joint Signs Among Unaffected First-Degree Relatives of Rheumatoid Arthritis Patients: Results From Studies of the Etiology of Rheumatoid Arthritis.

OBJECTIVE: To examine whether genetic, environmental, and serologic rheumatoid arthritis (RA) risk factors are associated with inflammatory joint signs in a cohort of first-degree relatives (FDRs) of RA patients. METHODS: We evaluated RA risk factors and inflammatory joint signs in a prospective cohort of FDRs without RA in the Studies of the Etiology of RA. Genetic factors included 5 HLA-DRB1 shared epitope alleles and 45 RA-associated single-nucleotide polymorphisms; loci were combined using genetic risk scores weighted by RA risk. Environmental factors (smoking, body mass index, education, and parity) and RA-related autoantibodies were assessed at baseline. Physical examination was performed at baseline and 2-year follow-up, by observers who were blinded with regard to autoantibody status, to assess inflammatory joint signs as tender or swollen joints at sites typical for RA. Logistic regression was performed to evaluate associations of genetic, environmental, and serologic factors with inflammatory joint signs. RESULTS: We analyzed 966 non-Hispanic white FDRs at baseline and 262 at 2-year follow-up after excluding those with inflammatory joint signs at baseline. The mean ± SD age was 47.2 ± 15.5 years, 71% were female, and 55% were shared epitope positive. Smoking >10 pack-years was associated with inflammatory joint signs at baseline (odds ratio [OR] 1.89 [95% confidence interval (95% CI) 1.26-2.82]) and at 2 years (OR 2.66 [95% CI 1.01-7.03]), compared to never smokers. There was a significant interaction between smoking and age with regard to risk of inflammatory joint signs (P = 0.02). FDRs younger than 50 years with >10 pack-years had the highest risk of inflammatory joint signs (OR 4.39 [95% CI 2.22-8.66], compared to never smokers younger than 50 years). CONCLUSION: In a high-risk cohort of FDRs, smoking and age were associated with both prevalent and incident inflammatory joint signs at sites typical for RA. Further prospective investigations of the factors affecting the transitions between preclinical RA phases are warranted.

Lower omega-3 fatty acids are associated with the presence of anti-cyclic citrullinated peptide autoantibodies in a population at risk for future rheumatoid arthritis: a nested case-control study.

OBJECTIVE: The aim of this study was to investigate omega-3 fatty acid (FA) supplement use and omega-3 FAs in erythrocyte membranes [omega-3 FA % in erythrocyte membranes (RBC)] and their association with anti-CCP autoantibodies in a population without RA, but who are at genetic risk for RA. METHODS: The multicentre Studies of the Etiology of RA (SERA) cohort includes RA-free subjects who are first-degree relatives of RA probands or are enriched with the HLA-DR4 allele. In a nested case-control study, 30 SERA cases were identified who were anti-CCP2 antibody positive. We further identified 47 autoantibody negative controls, frequency matched to cases on age at study visit, sex, race and study site. Anti-CCP2 status, self-reported omega-3 FA supplement use and omega-3 FA % in RBCs were obtained from a single visit. RESULTS: Anti-CCP2 positive cases were less likely than controls to report omega-3 FA supplement use (odds ratio: 0.14; 95% CI 0.03, 0.68). In addition, the likelihood of anti-CCP2 positivity was inversely associated with total omega-3 FA % in RBCs (odds ratio: 0.47; 95% CI 0.24, 0.92, for a s.d. increase). CONCLUSION: The inverse association between anti-CCP2 positivity and self-reported omega-3 FA supplement use and omega-3 FA % in RBCs suggests that omega-3 FAs may protect against the development of RA-related autoimmunity in pre-clinical RA.

Anti-carbamylated protein antibodies are present prior to rheumatoid arthritis and are associated with its future diagnosis.

OBJECTIVE: Anti-carbamylated protein (anti-CarP) antibodies could further elucidate early rheumatoid arthritis (RA) pathogenesis and predict clinical disease. We compared the diagnostic accuracy of anti-CarP antibodies for future RA to other RA-related antibodies in military personnel. METHODS: Stored pre-RA diagnosis serum samples from 76 RA cases were tested for anti-CarP fetal calf serum (FCS), anti-CarP fibrinogen (Fib), anticyclic citrullinated peptide antibodies version 2 (anti-CCP2), rheumatoid factor-nephelometry (RF-Neph), and RF isotypes [immunoglobulin M (IgM), IgG, and IgA]. Positivity for all antibodies was determined as ≥ 2 SD of log-transformed means from controls. Relationships between autoantibodies and future RA were assessed in prediagnosis serum for all RA cases compared to controls using sensitivity, specificity, and logistic regression. Differences in diagnostic accuracy between antibody combinations were assessed using comparisons of area under the curves (AUC). RESULTS: Anti-CarP-FCS was 26% sensitive and 95% specific for future RA, whereas anti-CarP-Fib was 16% sensitive and 95% specific for future RA. Anti-CarP-FCS positivity was associated with future RA, while anti-CarP-Fib trended toward association. The antibody combination of anti-CCP2 and/or ≥ 2 RF (RF-Neph and/or RF-isotypes) resulted in an AUC of 0.72 for future RA, where the AUC was 0.71 with the addition of anti-CarP-FCS to this prior combination. CONCLUSION: Adding anti-CarP-FCS to antibody combinations did not improve AUC. However, anti-CarP-FCS was associated with future onset of RA, and was present in prediagnosis serum in ∼10% of RA cases negative for anti-CCP2 but positive for RF.

Relationship between air pollution and positivity of RA-related autoantibodies in individuals without established RA: a report on SERA.

INTRODUCTION: Studies suggest that respiratory exposures including smoking, proximity to traffic and air pollution might be associated with development of rheumatoid arthritis (RA). RA-related autoantibodies are predictive of the development of RA. OBJECTIVE: We evaluated the relationship between RA-related autoantibodies and exposure to particulate matter (PM), a measure of air pollution of interest to health, in individuals without RA. METHODS: The Studies of the Etiology of Rheumatoid Arthritis (SERA) is a multicentre study following first-degree relatives (FDRs) of a proband with RA. FDRs are without the 1987 ACR (American College of Rheumatology) classifiable RA at enrolment and are followed for the development of RA-related autoimmunity. RA-related autoantibody outcomes as well as tender and swollen joint outcomes were assessed. Exposure to PM was assigned using ambient air pollution monitoring data and interpolated with inverse distance weighting spatial analyses using Geographic Information Systems. PM exposures were linked to FDR's residential zip codes. RESULTS: RA-related autoantibodies as well as tender or swollen joints are not associated with ambient PM concentrations. DISCUSSION: While other respiratory exposures may be associated with increased risk of RA, our data suggest that ambient PM is not associated with autoantibodies and joint signs among individuals without RA, but at increased risk of developing RA.