The impact of gender on time to rheumatoid arthritis classification: a retrospective analysis of a population-based cohort.

The objective is to compare the time to fulfillment of 1987 and 2010 ACR/EULAR classification criteria between female and male patients with rheumatoid arthritis (RA) and to assess the potential impact of gender on the time to DMARD therapy. Time from first provider-documented joint swelling to fulfillment of 1987 and 2010 ACR/EULAR criteria was measured in a population-based cohort of adults with incident RA, who were stratified by male or female gender. Disease characteristics, time to start of DMARD therapy, and choice of initial DMARD were compared between groups. The study included 214 patients with RA (148 females and 66 males). Median times from first joint swelling to fulfillment of 1987 (6.5 vs 2.5 days, p = 0.48) and 2010 (1 vs 0 days, p = 0.34) classification criteria were not different between female and male patients overall. There was no difference in time to first DMARD therapy in female vs male patients (15.5 vs 16 days, p = 0.90), and methotrexate was used most frequently as first DMARD in both genders (61% female vs 64% male, p = 0.76). Among the 49 female and 20 male RF/ACPA-negative patients, females experienced a higher median time from first joint swelling to fulfillment of the 1987 (65 vs 11 days, p = 0.063) and 2010 (65 vs 0 days, p = 0.035) classification criteria. Overall, there was no significant delay in meeting 1987 and 2010 ACR/EULAR classification criteria between female and male RA patients, though time to meeting both 1987 and 2010 criteria was slightly longer in males compared with females. Among seronegative patients, females experienced a significant delay to meeting 2010 criteria from first clinically detected synovitis.

Using Unsupervised Machine Learning Methods to Cluster Comorbidities in a Population-Based Cohort of Patients With Rheumatoid Arthritis.

OBJECTIVE: To identify clusters of comorbidities in patients with rheumatoid arthritis (RA) using 4 methods and to compare to patients without RA. METHODS: In this retrospective, population-based study, residents of 8 Minnesota counties with prevalent RA as of January 1, 2015 were identified. Age-, sex-, and county-matched non-RA comparators were selected from the same underlying population. Diagnostic codes were retrieved for 5 years before January 1, 2015. Using 2 codes ≥30 days apart, 44 previously defined morbidities and 11 nonoverlapping chronic disease categories based on Clinical Classifications Software were defined. Unsupervised machine learning methods of interest included hierarchical clustering, factor analysis, K-means clustering, and network analysis. RESULTS: Two groups of 1,643 patients with and without RA (72% female; mean age 63.1 years in both groups) were studied. Clustering of comorbidities revealed strong associations among mental/behavioral comorbidities and among cardiovascular risk factors and diseases. The clusters were associated with age and sex. Differences between the 4 clustering methods were driven by comorbidities that are rare and those that were weakly associated with other comorbidities. Common comorbidities tended to group together consistently across approaches. The instability of clusters when using different random seeds or bootstrap sampling impugns the usefulness and reliability of these methods. Clusters of common comorbidities between RA and non-RA cohorts were similar. CONCLUSION: Despite the higher comorbidity burden in patients with RA compared to the general population, clustering comorbidities did not identify substantial differences in comorbidity patterns between the RA and non-RA cohorts. The instability of clustering methods suggests caution when interpreting clustering using 1 method.

Comprehensive assessment of multimorbidity burden in a population-based cohort of patients with rheumatoid arthritis.

OBJECTIVE: To comprehensively assess multimorbidity burden in patients with rheumatoid arthritis (RA) in order to unify the multimorbidity definition for RA research and clinical practice. METHODS: In this population-based study, residents of eight Minnesota counties with prevalent RA on 1 January 2015 were identified. Age, sex and county-matched non-RA comparators were selected from the same population. Diagnostic codes were retrieved for 5 years before 1 January 2015. Using two codes ≥30 days apart, 44 previously defined morbidities and 78 non-overlapping chronic disease categories based on Clinical Classification Software were defined. Prevalence of each morbidity in the RA versus non-RA cohorts was compared using false discovery rate to adjust for multiple comparisons. Morbidities more common in RA than non-RA and those with prevalence ≥5% were retained. RESULTS: 1643 patients with RA and 1643 non-RA subjects (72% women; mean age 63.1 years) were studied. Using the 44 morbidities, multimorbidity (defined as 2+ morbidities) was present in 1411 (86%) of RA and 1164 (71%) of non-RA subjects (p<0.001) with 5+ morbidities present in 907 (55%) of RA and 619 (38%) of non-RA (p<0.001). Patients with RA had significantly higher prevalence of 24 of the 44 morbidities compared with non-RA, especially interstitial lung disease, fibromyalgia, osteoarthritis and osteoporosis. Among the additional 78 categories, 7 were significantly higher in RA than non-RA, including organic sleep disorders, vitamin D deficiency and foot ulcers. CONCLUSION: Patients with RA have a higher prevalence of multimorbidity compared with non-RA subjects. These results confirm the list of 44 morbidities and add several other morbidities of interest in RA.

Full-field digital mammographic interpretation with prior analog versus prior digitized analog mammography: time for interpretation.

OBJECTIVE: The purpose of our study was to quantitatively compare the time for interpretation of screening full-field digital mammography (FFDM) images using prior analog film mammograms for comparison versus digitized prior analog mammograms. MATERIALS AND METHODS: Images from 100 FFDM studies were interpreted by four radiologists. All FFDM images had comparison analog mammograms obtained a minimum of 1 year earlier that were digitized using a 43-µm film digitizer. Initially, the FFDM images were interpreted using the digitized prior mammogram on two, 5-megapixel monitors and PACS. All available PACS tools could be used. Four weeks later, the same 100 screening FFDMs were interpreted using the original analog mammograms on an alternator at 90° to the monitors used to interpret the screening FFDMs. The interpretation times were recorded and compared. The results were compared and evaluated for statistical significance using statistical software, with statistical significance set at p < 0.05. RESULTS: For each radiologist, the mean reading time for FFDM with digitized priors was significantly shorter in length in comparison with the mean reading time calculated for interpreting FFDM using analog film priors. The differences in times recorded between digitized analog versus analog ranged from 11.31 to 74.18 seconds. The reading times for the four readers ranged from 17.32 to 185.94 seconds, with a mean of 58.56 seconds when using analog film prior mammograms. When using digitized analog prior mammograms, the reading times for the four readers ranged from 11.32 to 109.11 seconds with a mean of 39.76 seconds. The average difference in reading time was calculated to be 18.80 seconds, showing that there is a 32% increase in interpretation speed when using a digitized prior analog for comparison studies as opposed to an analog prior. CONCLUSION: There is a statistically significant 32.1% average improvement in interpretation time when FFDM screening mammograms use digitized analog comparison mammograms than if FFDM is interpreted with the original analog film mammograms. This should allow more FFDMs to be interpreted in the same amount of time if digitized prior analog mammograms are used.

Epidemiology and Trends in Survival of Systemic Sclerosis in Olmsted County (1980-2018): A Population-based Study.

Background/Purpose: To update the epidemiology of systemic sclerosis (SSc) and evaluate the performance of the ACR/EULAR 2013 vs. 1980 ARA classification criteria in a U.S. population-based cohort. Methods: An inception cohort of patients with incident SSc from January 1, 1980, through December 31, 2018, in Olmsted County, Minnesota, was identified based on comprehensive individual medical record review. Incidence and prevalence rates were age- and sex-adjusted to the 2010 US white population. Survival rates were compared with expected rates in the general population. Fulfillment of 1980 and 2013 classification criteria was ascertained. Results: A total of 85 incident cases of SSc (91% female, mean age 55.4 ± 16 y) and 49 prevalent cases on Jan 1, 2015 were identified. The overall age- and sex-adjusted annual incidence was 25 (95% CI 20-31) per million population, with no change in incidence over time. The age- and sex-adjusted prevalence was 436 (95% CI: 313-558) per 1,000,000 population. 77 (91%) patients fulfilled the 2013 classification criteria, and 38 (45%) fulfilled the 1980 criteria. Mortality among patients with SSc was significantly higher in comparison to the general population, with a standardized mortality ratio of 2.48 (95% CI:1.76-3.39) and no evidence of improvement over time. Conclusions: SSc developed in 25 persons/million/year with no change over the 39-year study period. The 2013 classification criteria perform significantly better than the 1980 criteria but failed to classify 9% of patients. SSc portends a 2.5-fold higher risk of mortality than the general population, with no evidence of improved survival over time.

Hospitalization Rates Are Highest in the First 5 Years of Systemic Sclerosis: Results From a Population-based Cohort (1980-2016).

OBJECTIVE: Few studies have estimated the healthcare resource usage of patients with systemic sclerosis (SSc). The purpose of this study was to compare hospitalization among incident cases of SSc vs age- and sex-matched comparators. METHODS: A retrospective, population-based cohort of patients with SSc in Olmsted County, Minnesota, from January 1, 1980, to December 31, 2016, was assembled. A 2:1 cohort of age- and sex-matched patients without SSc from the same population was randomly selected for comparison. All hospitalizations in the geographic area from January 1, 1987, to September 30, 2018, were obtained. Rates of hospitalization, lengths of stay, and readmissions were compared between groups. RESULTS: There were 76 incident SSc cases and 155 non-SSc comparators (mean age 56 ± 16 yrs at diagnosis/index, 91% female) included. Rates of hospitalization among cases and comparators were 31.9 and 17.9 per 100 person-years, respectively (rate ratio [RR] 1.78, 95% CI 1.52-2.08). Hospitalization rates were higher in patients with SSc than comparators during the first 5 years after SSc diagnosis (RR 2.16, 95% CI 1.70-2.74). This difference decreased over time and was no longer significant at ≥ 15 years after SSc incidence/index. Lengths of stay (median [IQR] 4 [2-6] vs 3 [2-6], P = 0.52) and readmission rates (25% vs 23%, P = 0.51) were similar between groups. CONCLUSION: Patients with SSc were hospitalized more frequently than comparators, indicating high inpatient care needs in this population. Hospitalization rates were highest during the first 5 years following SSc diagnosis.

Rituximab Therapy for Systemic Rheumatoid Vasculitis: Indications, Outcomes, and Adverse Events.

OBJECTIVE: To characterize the indication, outcomes, and adverse effects of rituximab (RTX) treatment in a large single-center cohort of patients with systemic rheumatoid vasculitis (RV). METHODS: We retrospectively reviewed the medical charts of 17 patients treated with RTX for systemic RV from 2000 to 2017. Clinical characteristics, outcomes, and adverse effects were analyzed. RESULTS: At RV diagnosis, mean age was 59 years, 59% were female, 94% were white, and 82% had positive rheumatoid factor. At the time of initiating RTX, median Birmingham Vasculitis Activity Score for rheumatoid arthritis was 4.0 (interquartile range 2.0-7.5). RV presented in the skin in 8 patients (47%), as mononeuritis multiplex in 2 (12%), inflammatory ocular disease in 2 (12%), and affected multiple organ systems in 5 (29%). RTX was used for induction therapy in 8 patients (47%), relapsing RV in 4 (24%), second-line therapy in 2 (12%), and salvage therapy or in combination with another agent in 3 (18%). At 3 months, 2 (13%) of 15 patients with available followup information achieved complete remission (CR), and 10 (67%) achieved partial response (PR). At 6 months, 6 patients (40%) achieved CR, 8 (53%) achieved PR, and one had no response. At 12 months, 8 of 13 patients with available records (62%) had CR and 5 patients (38%) had PR. CONCLUSION: Systemic RV is difficult to treat effectively. CR of RV was achieved in 62% and PR in 38% of patients within 12 months of RTX use. Further evidence is needed to inform treatment for patients with RV.

Evidence of Diagnostic and Treatment Delay in Seronegative Rheumatoid Arthritis: Missing the Window of Opportunity.

OBJECTIVES: To compare the time from first joint swelling to fulfillment of the American College of Rheumatology/European League Against Rheumatism classification criteria between patients with seropositive and seronegative rheumatoid arthritis (RA) and to assess the impact of seronegative status on the time from first joint swelling to initiation of disease-modifying antirheumatic drug (DMARD) therapy and achievement of remission. PATIENTS AND METHODS: Times from first provider-documented joint swelling to fulfillment of the 1987 and 2010 American College of Rheumatology/European League Against Rheumatism criteria and to the clinical diagnosis of RA were measured in a population-based cohort of adults with incident RA between January 1, 2009, and December 31, 2014. Disease characteristics and achievement of remission were compared between seropositive (rheumatoid factor positive and/or anti-citrullinated peptide antibody positive) and seronegative (rheumatoid factor negative/anti-citrullinated peptide antibody negative) patients. RESULTS: The median time from first joint swelling to fulfillment of the 1987 (48 [interquartile range (IQR), 0-300] days vs 2 [IQR, 0-45] days; P=.001) and 2010 (14 [IQR, 0-196] days vs 0 [IQR, 0-29] days; P=.004) classification criteria and the median time from first joint swelling to the clinical diagnosis of RA (187 [IQR, 13-503] days vs 11 [IQR, 0-76] days; P<.001) were significantly longer in seronegative patients than in seropositive patients. The median time from first joint swelling to first prescribed DMARD therapy was significantly longer in seronegative patients (40 [IQR, 5-199] days vs 14 [IQR, 0-73] days; P=.01). Patients with seronegative RA were less likely to achieve remission (28% vs 50% at 5 years after fulfillment of the 2010 criteria; P=.007), but there was no difference when the patient global score was removed from the remission definition. CONCLUSION: Patients with seronegative RA experienced a delay in diagnosis, according to both the 1987 and 2010 classification criteria, as well as a delay in the initiation of DMARD therapy. Patients with seronegative RA were also less likely to attain remission, suggesting that the window of opportunity for intervention may be more frequently missed in this group.

Breast-Specific γ-Imaging for the Detection of Mammographically Occult Breast Cancer in Women at Increased Risk.

UNLABELLED: Breast-specific γ-imaging (BSGI) is a physiologic imaging modality that can detect subcentimeter and mammographically occult breast cancer, with a sensitivity and specificity comparable to MRI. The purpose of this study was to determine the incremental increase in breast cancer detection when BSGI is used as an adjunct to mammography in women at increased risk for breast cancer. METHODS: All patients undergoing BSGI from April 2010 through January 2014 were retrospectively reviewed. Eligible patients were identified as women at increased risk for breast cancer and whose most recent mammogram was benign. Examinations exhibiting focally increased radiotracer uptake were considered positive. Incremental increase in cancer detection was calculated as the percentage of mammographically occult BSGI-detected breast cancer and the number of mammographically occult breast cancers detected per 1,000 women screened. RESULTS: Included in this study were 849 patients in whom 14 BSGI examinations detected mammographically occult breast cancer. Patients ranged in age from 26 to 83 y, with a mean age of 57 y. Eleven of 14 cancers were detected in women with dense breasts. The addition of BSGI to the annual breast screen of asymptomatic women at increased risk for breast cancer yields 16.5 cancers per 1,000 women screened. When high-risk lesions and cancers were combined, BSGI detected 33.0 high-risk lesions and cancers per 1,000 women screened. CONCLUSION: BSGI is a reliable adjunct modality to screening mammography that increases breast cancer detection by 1.7% (14/849) in women at increased risk for breast cancer, comparable to results reported for breast MRI. BSGI is beneficial in breast cancer detection in women at increased risk, particularly in those with dense breasts.

Novel oxytocin gene expression in the hindbrain is induced by alcohol exposure: transgenic zebrafish enable visualization of sensitive neurons.

BACKGROUND: Fetal Alcohol Spectrum Disorders (FASD) are a collection of disorders resulting from fetal ethanol exposure, which causes a wide range of physical, neurological and behavioral deficits including heightened susceptibility for alcoholism and addictive disorders. While a number of mechanisms have been proposed for how ethanol exposure disrupts brain development, with selective groups of neurons undergoing reduced proliferation, dysfunction and death, the induction of a new neurotransmitter phenotype by ethanol exposure has not yet been reported. PRINCIPAL FINDINGS: The effects of embryonic and larval ethanol exposure on brain development were visually monitored using transgenic zebrafish expressing cell-specific green fluorescent protein (GFP) marker genes. Specific subsets of GFP-expressing neurons were highly sensitive to ethanol exposure, but only during defined developmental windows. In the med12 mutant, which affects the Mediator co-activator complex component Med12, exposure to lower concentrations of ethanol was sufficient to reduce GFP expression in transgenic embryos. In transgenic embryos and larva containing GFP driven by an oxytocin-like (oxtl) promoter, ethanol exposure dramatically up-regulated GFP expression in a small group of hindbrain neurons, while having no effect on expression in the neuroendocrine preoptic area. CONCLUSIONS: Alcohol exposure during limited embryonic periods impedes the development of specific, identifiable groups of neurons, and the med12 mutation sensitizes these neurons to the deleterious effects of ethanol. In contrast, ethanol exposure induces oxtl expression in the hindbrain, a finding with profound implications for understanding alcoholism and other addictive disorders.

Breast-specific gamma imaging in the detection of atypical ductal hyperplasia and lobular neoplasia.

RATIONALE AND OBJECTIVES: Atypical lesions such as atypical ductal hyperplasia (ADH) and lobular neoplasia are nonmalignant lesions that are associated with significant increased risk of developing breast cancer. Atypical lesions have been reported to present with focal increased radiotracer uptake on breast-specific gamma imaging (BSGI) examination, a novel physiologic tool for the detection of breast cancer. To date the sensitivity of BSGI in the detection of atypical lesions has not been reported. The purpose of this study is to determine the sensitivity of BSGI in detecting ADH and lobular neoplasia. MATERIALS AND METHODS: A total of 1316 patients who received a BSGI exam between January 2006 and July 2009 were retrospectively reviewed. All patients who underwent minimally invasive biopsy and subsequent surgical excision where the highest pathology was solely ADH or lobular neoplasia (reported as ALH, lobular carcinoma in situ or lobular neoplasia), according to the pathology database were included (n = 15). The sensitivity was determined as the percentage of positive BSGI exams out of all patients diagnosed with ADH or lobular neoplasia who received a BSGI. RESULTS: Patient ages ranged from 39 to 67 (mean, 52). Eight of 15 patients had ADH, 6/15 lobular neoplasia, and 1/15 ADH and lobular neoplasia in one lesion. Fifteen of the 15 (100%) patients with surgically confirmed ADH or lobular neoplasia had a positive BSGI, with focally increased radiotracer uptake at the site of the verified high-risk lesion. CONCLUSION: BSGI has a high sensitivity for the detection of atypical, high-risk breast lesions. A diagnosis of an atypical lesion is concordant with focal increased radiotracer uptake with BSGI and can identify women at increased risk for breast cancer.