Patterns of Tumor Necrosis Factor Inhibitor (TNFi) Biosimilar Use Across United States Rheumatology Practices.

ObjectiveIt is unclear if biosimilars of biologics for inflammatory arthritis are realizing their promise to increase competition and improve accessibility. This study evaluates biosimilar tumor necrosis factor inhibitor (TNFi) utilization across rheumatology practices in the United States and compares whether patients initiating biosimilars remain on these treatments at least as long as new initiators of bio-originators.MethodsWe identified a cohort of patients initiating a TNFi biosimilar between January 2017 and September 2018 from an electronic health record registry containing data from 218 rheumatology practices and over 1 million rheumatology patients in the United States. We also identified a cohort of patients who initiated the bio-originator TNFi during the same period. We calculated the proportion of biosimilar prescriptions compared with other TNFi's and compared persistence on these therapies, adjusting for age, sex, diagnoses codes, and insurance type.ResultsWe identified 909 patients prescribed the biosimilar infliximab-dyyb, the only biosimilar prescribed, and 4413 patients with a new prescription for the bio-originator infliximab. Biosimilar patients tended to be older, have a diagnosis code for rheumatoid arthritis, and covered by Medicare insurance. Over the study period, biosimilar prescriptions reached a maximum of 3.5% of all TNFi prescriptions. Patients persisted on the biosimilar at least as long as the bio-originator infliximab (hazard ratio [HR] 0.83, P = 0.07).ConclusionThe uptake of biosimilars in the United States remains low despite persistence on infliximab-dyyb being similar to the infliximab bio-originator. These results add to clinical studies that should provide greater confidence to patients and physicians regarding biosimilar use

CO\u3csub\u3e2\u3c/sub\u3e-Fixing One-Carbon Metabolism in a Cellulose-Degrading Bacterium \u3cem\u3eClostridium thermocellum\u3c/em\u3e

Clostridium thermocellum can ferment cellulosic biomass to formate and other end products, including CO2. This organism lacks formate dehydrogenase (Fdh), which catalyzes the reduction of CO2 to formate. However, feeding the bacterium 13C-bicarbonate and cellobiose followed by NMR analysis showed the production of 13C-formate in C. thermocellum culture, indicating the presence of an uncharacterized pathway capable of converting CO2 to formate. Combining genomic and experimental data, we demonstrated that the conversion of CO2 to formate serves as a CO2 entry point into the reductive one-carbon (C1) metabolism, and internalizes CO2 via two biochemical reactions: the reversed pyruvate: ferredoxin oxidoreductase (rPFOR), which incorporates CO2 using acetyl-CoA as a substrate and generates pyruvate, and pyruvate- formate lyase (PFL) converting pyruvate to formate and acetyl-CoA. We analyzed the labeling patterns of proteinogenic amino acids in individual deletions of all five putative PFOR mutants and in a PFL deletion mutant. We identified two enzymes acting as rPFOR, confirmed the dual activities of rPFOR and PFL crucial for CO2 uptake, and provided physical evidence of a distinct in vivo “rPFOR-PFL shunt” to reduce CO2 to formate while circumventing the lack of Fdh. Such a pathway precedes CO2 fixation via the reductive C1 metabolic pathway in C. thermocellum. These findings demonstrated the metabolic versatility of C. thermocellum, which is thought of as primarily a cellulosic heterotroph but is shown here to be endowed with the ability to fix CO2 as well

Genetic Risk Score Predicting Risk of Rheumatoid Arthritis Phenotypes and Age of Symptom Onset

Cumulative genetic profiles can help identify individuals at high-risk for developing RA. We examined the impact of 39 validated genetic risk alleles on the risk of RA phenotypes characterized by serologic and erosive status.We evaluated single nucleotide polymorphisms at 31 validated RA risk loci and 8 Human Leukocyte Antigen alleles among 542 Caucasian RA cases and 551 Caucasian controls from Nurses' Health Study and Nurses' Health Study II. We created a weighted genetic risk score (GRS) and evaluated it as 7 ordinal groups using logistic regression (adjusting for age and smoking) to assess the relationship between GRS group and odds of developing seronegative (RF- and CCP-), seropositive (RF+ or CCP+), erosive, and seropositive, erosive RA phenotypes. In separate case only analyses, we assessed the relationships between GRS and age of symptom onset. In 542 RA cases, 317 (58%) were seropositive, 163 (30%) had erosions and 105 (19%) were seropositive with erosions. Comparing the highest GRS risk group to the median group, we found an OR of 1.2 (95% CI = 0.8-2.1) for seronegative RA, 3.0 (95% CI = 1.9-4.7) for seropositive RA, 3.2 (95% CI = 1.8-5.6) for erosive RA, and 7.6 (95% CI = 3.6-16.3) for seropositive, erosive RA. No significant relationship was seen between GRS and age of onset.Results suggest that seronegative and seropositive/erosive RA have different genetic architecture and support the importance of considering RA phenotypes in RA genetic studies

TYK2 Protein-Coding Variants Protect against Rheumatoid Arthritis and Autoimmunity, with No Evidence of Major Pleiotropic Effects on Non-Autoimmune Complex Traits

Despite the success of genome-wide association studies (GWAS) in detecting a large number of loci for complex phenotypes such as rheumatoid arthritis (RA) susceptibility, the lack of information on the causal genes leaves important challenges to interpret GWAS results in the context of the disease biology. Here, we genetically fine-map the RA risk locus at 19p13 to define causal variants, and explore the pleiotropic effects of these same variants in other complex traits. First, we combined Immunochip dense genotyping (n = 23,092 case/control samples), Exomechip genotyping (n = 18,409 case/control samples) and targeted exon-sequencing (n = 2,236 case/controls samples) to demonstrate that three protein-coding variants in TYK2 (tyrosine kinase 2) independently protect against RA: P1104A (rs34536443, OR = 0.66, P = 2.3x10-21), A928V (rs35018800, OR = 0.53, P = 1.2x10-9), and I684S (rs12720356, OR = 0.86, P = 4.6x10-7). Second, we show that the same three TYK2 variants protect against systemic lupus erythematosus (SLE, Pomnibus = 6x10-18), and provide suggestive evidence that two of the TYK2 variants (P1104A and A928V) may also protect against inflammatory bowel disease (IBD; Pomnibus = 0.005). Finally, in a phenomewide association study (PheWAS) assessing >500 phenotypes using electronic medical records (EMR) in >29,000 subjects, we found no convincing evidence for association of P1104A and A928V with complex phenotypes other than autoimmune diseases such as RA, SLE and IBD. Together, our results demonstrate the role of TYK2 in the pathogenesis of RA, SLE and IBD, and provide supporting evidence for TYK2 as a promising drug target for the treatment of autoimmune diseases

Thromboprophylaxis Is Associated With Reduced Post-hospitalization Venous Thromboembolic Events in Patients With Inflammatory Bowel Diseases

Background & Aims Patients with inflammatory bowel diseases (IBDs) have increased risk for venous thromboembolism (VTE); those who require hospitalization have particularly high risk. Few hospitalized patients with IBD receive thromboprophylaxis. We analyzed the frequency of VTE after IBD-related hospitalization, risk factors for post-hospitalization VTE, and the efficacy of prophylaxis in preventing post-hospitalization VTE. Methods In a retrospective study, we analyzed data from a multi-institutional cohort of patients with Crohn's disease or ulcerative colitis and at least 1 IBD-related hospitalization. Our primary outcome was a VTE event. All patients contributed person-time from the date of the index hospitalization to development of VTE, subsequent hospitalization, or end of follow-up. Our main predictor variable was pharmacologic thromboprophylaxis. Cox proportional hazard models adjusting for potential confounders were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results From a cohort of 2788 patients with at least 1 IBD-related hospitalization, 62 patients developed VTE after discharge (2%). Incidences of VTE at 30, 60, 90, and 180 days after the index hospitalization were 3.7/1000, 4.1/1000, 5.4/1000, and 9.4/1000 person-days, respectively. Pharmacologic thromboprophylaxis during the index hospital stay was associated with a significantly lower risk of post-hospitalization VTE (HR, 0.46; 95% CI, 0.22–0.97). Increased numbers of comorbidities (HR, 1.30; 95% CI, 1.16–1.47) and need for corticosteroids before hospitalization (HR, 1.71; 95% CI, 1.02–2.87) were also independently associated with risk of VTE. Length of hospitalization or surgery during index hospitalization was not associated with post-hospitalization VTE. Conclusions Pharmacologic thromboprophylaxis during IBD-related hospitalization is associated with reduced risk of post-hospitalization VTE.National Institutes of Health (U.S.) (U54-LM008748

The Relation of FIMR Programs and Other Perinatal Systems Initiatives with Maternal and Child Health Activities in the Community

Objectives : To evaluate the association of the presence of a fetal and infant mortality review (FIMR) program, other perinatal systems initiative (PSI), or both in a community with the performance of essential maternal and child health (MCH) services by local health departments (LHDs). Methods : Data were obtained from telephone interviews with professionals from LHDs across the United States. Logistic regression was used to estimate the odds of a LHD conducting each essential MCH service in communities with and without FIMR programs or with and without PSIs, adjusted for geographic area. Results : Of the 193 communities in the sample, 41 had only a FIMR program, 36 had only a PSI, 47 had both programs, and 69 had neither. The presence of a FIMR was related to greater performance of essential MCH services in LHDs in six areas: data assessment and analysis; client services and access; quality assurance and improvement; community partnerships and mobilization; policy development; and enhancement of capacity of the health care work force. Similar findings were noted for the same broad essential services for PSIs. The comparisons of LHDs in FIMR and non-FIMR communities, however, showed greater involvement of communities with a FIMR program in essential MCH services related to data collection and quality assurance than were found for comparisons of LHDs in communities with and without a PSI. The presence of a PSI was uniquely associated with conducting needs assessments for pregnant women and infants, participation in coalitions for infants, promoting access for uninsured women to private providers and involving local officials and agencies in health plans for both populations. When both programs were present, LHDs had a greater odds of engaging in essential MCH services related to assessment and monitoring of the health of the population, reporting on progress in meeting the health needs of pregnant women and infants, and presenting data to local political officials than when either program alone was in the community. Conclusions : Local health departments in communities with FIMR programs or PSIs appear to be more likely to conduct essential MCH services in the community. Some of these relations are unique to FIMR, particularly for data collection and quality assurance services, and some are unique to PSIs, for example those that involve interaction with other community agencies or groups. Performance of the essential MCH services also appears to be enhanced when both a FIMR program and a PSI are present in the community.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45329/1/10995_2004_Article_496297.pd

Association between inflammation and systolic blood pressure in RA compared to patients without RA

Background: The relationship between inflammation and blood pressure (BP) has been studied mainly in the general population. In this study, we examined the association between inflammation and BP across a broader range of inflammation observed in rheumatoid arthritis (RA) and non-RA outpatients. Methods: We studied subjects from a tertiary care outpatient population with C-reactive protein (CRP) and BP measured on the same date in 2009–2010; RA outpatients were identified using a validated algorithm. General population data were obtained from the National Health and Nutrition Examination Survey (NHANES) as comparison. To study the cross-sectional association between CRP and BP in the three groups, we constructed a generalized additive model. Longitudinal association between CRP and BP was examined using a repeated-measures linear mixed-effects model in RA outpatients with significant change in inflammation at two consecutive time points. Results: We studied 24,325 subjects from the outpatient population, of whom 1811 had RA, and 5561 were from NHANES. In RA outpatients, we observed a positive relationship between CRP and systolic BP (SBP) at CRP < 6 mg/L and an inverse association at CRP ≥ 6 mg/L. A similar inverse U-shaped relationship was observed in non-RA outpatients. In NHANES, we observed a positive relationship between CRP and SBP as demonstrated by previous studies. Longitudinal analysis in RA showed that every 10 mg/L increase in CRP was associated with a 0.38 mmHg reduction in SBP. Conclusions: Across a broad range of CRP observed in RA and non-RA outpatients, we found an inverse U-shaped relationship between CRP and SBP, highlighting a relationship not previously observed when studying the general population. Electronic supplementary material The online version of this article (10.1186/s13075-018-1597-9) contains supplementary material, which is available to authorized users

Improving Case Definition of Crohnʼs Disease and Ulcerative Colitis in Electronic Medical Records Using Natural Language Processing

available in PMC 2014 June 01Background: Previous studies identifying patients with inflammatory bowel disease using administrative codes have yielded inconsistent results. Our objective was to develop a robust electronic medical record–based model for classification of inflammatory bowel disease leveraging the combination of codified data and information from clinical text notes using natural language processing. Methods: Using the electronic medical records of 2 large academic centers, we created data marts for Crohn’s disease (CD) and ulcerative colitis (UC) comprising patients with ≥1 International Classification of Diseases, 9th edition, code for each disease. We used codified (i.e., International Classification of Diseases, 9th edition codes, electronic prescriptions) and narrative data from clinical notes to develop our classification model. Model development and validation was performed in a training set of 600 randomly selected patients for each disease with medical record review as the gold standard. Logistic regression with the adaptive LASSO penalty was used to select informative variables. Results: We confirmed 399 CD cases (67%) in the CD training set and 378 UC cases (63%) in the UC training set. For both, a combined model including narrative and codified data had better accuracy (area under the curve for CD 0.95; UC 0.94) than models using only disease International Classification of Diseases, 9th edition codes (area under the curve 0.89 for CD; 0.86 for UC). Addition of natural language processing narrative terms to our final model resulted in classification of 6% to 12% more subjects with the same accuracy. Conclusions: Inclusion of narrative concepts identified using natural language processing improves the accuracy of electronic medical records case definition for CD and UC while simultaneously identifying more subjects compared with models using codified data alone.National Institutes of Health (U.S.) (NIH U54-LM008748)American Gastroenterological AssociationNational Institutes of Health (U.S.) (NIH K08 AR060257)Beth Isreal Deaconess Medical Center (Katherine Swan Ginsburg Fund)National Institutes of Health (U.S.) (NIH R01-AR056768)Burroughs Wellcome Fund (Career Award for Medical Scientists)National Institutes of Health (U.S.) (NIH U01-GM092691)National Institutes of Health (U.S.) (NIH R01-AR059648

Psychiatric co-morbidity is associated with increased risk of surgery in Crohn's disease

Psychiatric co-morbidity, in particular major depression and anxiety, is common in patients with Crohn's disease (CD) and ulcerative colitis (UC). Prior studies examining this may be confounded by the co-existence of functional bowel symptoms. Limited data exist examining an association between depression or anxiety and disease-specific endpoints such as bowel surgery.National Institutes of Health (U.S.) (NIH U54-LM008748)American Gastroenterological AssociationNational Institutes of Health (U.S.) (NIH K08 AR060257)Beth Isreal Deaconess Medical Center (Katherine Swan Ginsburg Fund)National Institutes of Health (U.S.) (NIH R01-AR056768)National Institutes of Health (U.S.) (NIH U01-GM092691)National Institutes of Health (U.S.) (NIH R01-AR059648)Burroughs Wellcome Fund (Career Award for Medical Scientists)National Institutes of Health (U.S.) (NIH K24 AR052403)National Institutes of Health (U.S.) (NIH P60 AR047782)National Institutes of Health (U.S.) (NIH R01 AR049880