A New Type 2 Diabetes Microsimulation Model to Estimate Long-Term Health Outcomes, Costs, and Cost-Effectiveness.

OBJECTIVES: This study aimed to develop a microsimulation model to estimate the health effects, costs, and cost-effectiveness of public health and clinical interventions for preventing/managing type 2 diabetes. METHODS: We combined newly developed equations for complications, mortality, risk factor progression, patient utility, and cost-all based on US studies-in a microsimulation model. We performed internal and external validation of the model. To demonstrate the model's utility, we predicted remaining life-years, quality-adjusted life-years (QALYs), and lifetime medical cost for a representative cohort of 10 000 US adults with type 2 diabetes. We then estimated the cost-effectiveness of reducing hemoglobin A1c from 9% to 7% among adults with type 2 diabetes, using low-cost, generic, oral medications. RESULTS: The model performed well in internal validation; the average absolute difference between simulated and observed incidence for 17 complications was < 8%. In external validation, the model was better at predicting outcomes in clinical trials than in observational studies. The cohort of US adults with type 2 diabetes was projected to have an average of 19.95 remaining life-years (from mean age 61), incur $187 729 in discounted medical costs, and accrue 8.79 discounted QALYs. The intervention to reduce hemoglobin A1c increased medical costs by $1256 and QALYs by 0.39, yielding an incremental cost-effectiveness ratio of $9103 per QALY. CONCLUSIONS: Using equations exclusively derived from US studies, this new microsimulation model achieves good prediction accuracy in US populations. The model can be used to estimate the long-term health impact, costs, and cost-effectiveness of interventions for type 2 diabetes in the United States.

State-Specific Prevalence of Depression Among Adults With and Without Diabetes - United States, 2011-2019.

INTRODUCTION: In 2019 among US adults, 1 in 9 had diagnosed diabetes and 1 in 5 had diagnosed depression. Since these conditions frequently coexist, compounding their health and economic burden, we examined state-specific trends in depression prevalence among US adults with and without diagnosed diabetes. METHODS: We used data from the 2011 through 2019 Behavioral Risk Factor Surveillance System to evaluate self-reported diabetes and depression prevalence. Joinpoint regression estimated state-level trends in depression prevalence by diabetes status. RESULTS: In 2019, the overall prevalence of depression in US adults with and without diabetes was 29.2% (95% CI, 27.8%-30.6%) and 17.9% (95% CI, 17.6%-18.1%), respectively. From 2011 to 2019, the depression prevalence was relatively stable for adults with diabetes (28.6% versus 29.2%) but increased for those without diabetes from 15.5% to 17.9% (average annual percent change [APC] over the 9-year period = 1.6%, P = .015). The prevalence of depression was consistently more than 10 percentage points higher among adults with diabetes than those without diabetes. The APC showed a significant increase in some states (Illinois: 5.9%, Kansas: 3.5%) and a significant decrease in others (Arizona: -5.1%, Florida: -4.0%, Colorado: -3.4%, Washington: -0.9%). In 2019, although it varied by state, the depression prevalence among adults with diabetes was highest in states with a higher diabetes burden such as Kentucky (47.9%), West Virginia (47.0%), and Maine (41.5%). CONCLUSION: US adults with diabetes are more likely to report prevalent depression compared with adults without diabetes. These findings highlight the importance of screening and monitoring for depression as a potential complication among adults with diabetes.

Prevalence of Testing for Diabetes Among US Adults With Overweight or Obesity, 2016-2019.

Introduction: Screening for prediabetes and type 2 diabetes may allow earlier detection, diagnosis, and treatment. The US Preventive Services Task Force recommends screening every 3 years for abnormal blood glucose among adults aged 40 to 70 years with overweight or obesity. Using IQVIA Ambulatory Electronic Medical Records, we estimated the proportion of adults aged 40 to 70 years with overweight or obesity who received blood glucose testing within 3 years from baseline in 2016. Methods: We identified 1,338,509 adults aged 40 to 70 years with overweight or obesity in 2016 and without pre-existing diabetes. We included adults whose records were present in the data set for at least 2 years before their index body mass index (BMI) in 2016 and 3 years after the index BMI (2017-2019), during which we examined the occurrence of blood glucose testing. We calculated the unadjusted and adjusted prevalence of receiving blood glucose testing. Results: The unadjusted prevalence of receiving blood glucose testing was 33.4% when it was defined as having a hemoglobin A1c or fasting plasma glucose measure. The unadjusted prevalence was 74.3% when we expanded the definition of testing to include random plasma glucose and unspecified glucose measures. Adults with obesity were more likely to receive the test than those with overweight. Men (vs women) and adults aged 50 to 59 years (vs other age groups) had higher testing rates. Conclusion: Our findings could inform clinical and public health promotion efforts to improve screening for blood glucose levels among adults with overweight or obesity.

Potential Indirect Effects of the COVID-19 Pandemic on Use of Emergency Departments for Acute Life-Threatening Conditions - United States, January-May 2020.

On March 13, 2020, the United States declared a national emergency in response to the coronavirus disease 2019 (COVID-19) pandemic. Subsequently, states enacted stay-at-home orders to slow the spread of SARS-CoV-2, the virus that causes COVID-19, and reduce the burden on the U.S. health care system. CDC* and the Centers for Medicare & Medicaid Services (CMS)† recommended that health care systems prioritize urgent visits and delay elective care to mitigate the spread of COVID-19 in health care settings. By May 2020, national syndromic surveillance data found that emergency department (ED) visits had declined 42% during the early months of the pandemic (1). This report describes trends in ED visits for three acute life-threatening health conditions (myocardial infarction [MI, also known as heart attack], stroke, and hyperglycemic crisis), immediately before and after declaration of the COVID-19 pandemic as a national emergency. These conditions represent acute events that always necessitate immediate emergency care, even during a public health emergency such as the COVID-19 pandemic. In the 10 weeks following the emergency declaration (March 15-May 23, 2020), ED visits declined 23% for MI, 20% for stroke, and 10% for hyperglycemic crisis, compared with the preceding 10-week period (January 5-March 14, 2020). EDs play a critical role in diagnosing and treating life-threatening conditions that might result in serious disability or death. Persons experiencing signs or symptoms of serious illness, such as severe chest pain, sudden or partial loss of motor function, altered mental state, signs of extreme hyperglycemia, or other life-threatening issues, should seek immediate emergency care, regardless of the pandemic. Clear, frequent, highly visible communication from public health and health care professionals is needed to reinforce the importance of timely care for medical emergencies and to assure the public that EDs are implementing infection prevention and control guidelines that help ensure the safety of their patients and health care personnel.

Disparities in Receipt of Eye Exams Among Medicare Part B Fee-for-Service Beneficiaries with Diabetes - United States, 2017.

Approximately 30 million persons in the United States have diabetes.* Persons with diabetes are at risk for vision loss from diabetic retinopathy and other eye diseases (1). Diabetic retinopathy, the most common diabetes-related eye disease, affects 29% of U.S. adults aged ≥40 years with diabetes (2) and is the leading cause of incident blindness among working-age adults (1). It is caused by chronically high blood glucose damaging blood vessels in the retina.† Annual dilated eye exams are recommended for persons with diabetes because early detection and timely treatment of diabetic eye diseases can prevent irreversible vision loss§,¶ (3,4). Studies have documented prevalence of annual eye exams among U.S. adults with diabetes (5,6); however, a lack of recent state-level data limits identification of geographic disparities in adherence to this recommendation. Medicare claims from the 50 states, the District of Columbia (DC), Puerto Rico, and U.S. Virgin Islands (USVI) were examined to assess the prevalence of eye exams in 2017 among beneficiaries with diabetes who were continuously enrolled in Part B fee-for-service insurance, which covers annual eye exams for beneficiaries with diabetes.** This report also examines disparities, by state and race/ethnicity, in receipt of eye exams. Nationally, 54.1% of beneficiaries with diabetes had an eye exam in 2017. Prevalence ranged from 43.9% in Puerto Rico to 64.8% in Rhode Island. Fewer than 50% of beneficiaries received an eye exam in seven states (Alabama, Alaska, Kentucky, Louisiana, Nevada, West Virginia, and Wyoming) and Puerto Rico. Non-Hispanic white (white) beneficiaries had a higher prevalence of receiving an eye exam (55.6%) than did non-Hispanic blacks (blacks) (48.9%) and Hispanics (48.2%). Barriers to receiving eye care (e.g., suboptimal clinical care coordination and referral, low health literacy, and lack of perceived need for care) might limit Medicare beneficiaries' ability to follow this preventive care recommendation. Understanding and addressing these barriers might prevent irreversible vision loss among persons with diabetes.

Diabetes Prevalence and Incidence Among Medicare Beneficiaries - United States, 2001-2015.

Diabetes affects approximately 12% of the U.S. adult population and approximately 25% of adults aged ≥65 years. From 2009 to 2017, there was no significant change in diabetes prevalence overall or among persons aged 65-79 years (1). However, these estimates were based on survey data with <5,000 older adults. Medicare administrative data sets, which contain claims for millions of older adults, afford an opportunity to explore both trends over time and heterogeneity within an older population. Previous studies have shown that claims data can be used to identify persons with diagnosed diabetes (2). This study estimated annual prevalence and incidence of diabetes during 2001-2015 using Medicare claims data for beneficiaries aged ≥68 years and found that prevalence plateaued after 2012 and incidence decreased after 2006. In 2015 (the most recent year estimated) prevalence was 31.6%, and incidence was 3.0%. Medicare claims can serve as an important source of data for diabetes surveillance for the older population, which can inform prevention and treatment strategies.

Changes in Alcohol Use after Metabolic and Bariatric Surgery: Predictors and Mechanisms.

PURPOSE OF REVIEW: This review synthesized the literature on predictors and mechanisms of post-bariatric alcohol problems, in order to guide future research on prevention and treatment targets. RECENT FINDINGS: Consistent evidence suggests an elevated risk of developing problems with alcohol following bariatric surgery. While there is a paucity of empirical data on predictors of problematic alcohol use after bariatric surgery, being male, a younger age, smoking, regular alcohol consumption, pre-surgical alcohol use disorder, and a lower sense of belonging have predicted alcohol misuse post-operatively. This review synthesizes potential mechanisms including specific bariatric surgical procedures, peptides and reinforcement/reward pathways, pharmacokinetics, and genetic influences. Finally, potential misperceptions regarding mechanisms are explored. Certain bariatric procedures elevate the risk of alcohol misuse post-operatively. Future research should serve to elucidate the complexities of reward signaling, genetically mediated mechanisms, and pharmacokinetics in relation to alcohol use across gender and developmental period by surgery type.

Burden of laboratory-confirmed shigellosis infections in Guatemala 2007-2012: results from a population-based surveillance system.

BACKGROUND: We describe the epidemiology and antimicrobial susceptibility patterns of culture-confirmed Shigella infections in facility-based surveillance sites in Guatemala. Current studies using quantitative molecular diagnostics suggest Shigella may contribute most to the global diarrheal disease burden. Since identification of Shigella requires culturing techniques using stool specimens and few laboratories in Guatemala routinely culture for this pathogen, little is known about the true burden of Shigella in Guatemala or, importantly, the antimicrobial resistance patterns. METHODS: Clinical, epidemiological, and laboratory data were collected on 5399 patients with acute diarrhea (≥3 loose stools in 24 h) from June 2007-August 2012. Multidrug resistance (MDR) was defined as resistance to ampicillin and trimethoprim/sulfamethoxazole. RESULTS: Five percent (261) of stool specimens yielded Shigella spp. The annual incidence of laboratory-confirmed infections ranged from 5.0 to 24.1 per 100,000 persons in Santa Rosa and 0.3 to 6.2 per 100,000 in Quetzaltenango; 58% of cases occurred in children < 5 years of age. Thirty patients were hospitalized; one patient died. Oral rehydration or intravenous solution was used to treat 72% of hospitalized and 15% of ambulatory cases. Fifty-nine percent of cases were S. flexneri and 51% of cases were MDR. CONCLUSIONS: Shigella is an important cause of bacterial diarrhea in children and prevalence of MDR highlights the importance of appropriate treatment regimens. This study demonstrates that strengthening laboratory capacity in Guatemala can help determine causes which can lead to prevention of diarrheal diseases, particularly in children. Such capacity building is also critical for rapid detection and control of public health threats at their source and therefore for global health security.

Trends in Diabetic Ketoacidosis Hospitalizations and In-Hospital Mortality - United States, 2000-2014.

Diabetes is a common chronic condition and as of 2015, approximately 30 million persons in the United States had diabetes (23 million with diagnosed and 7 million with undiagnosed) (1). Diabetic ketoacidosis (DKA) is a life-threatening but preventable complication of diabetes characterized by uncontrolled hyperglycemia (>250 mg/dL), metabolic acidosis, and increased ketone concentration that occurs most frequently in persons with type 1 diabetes (2). CDC's United States Diabetes Surveillance System* (USDSS) indicated an increase in hospitalization rates for DKA during 2009-2014, most notably in persons aged <45 years. To explore this finding, 2000-2014 data from the Agency for Healthcare Research and Quality's National Inpatient Sample (NIS)† were assembled to calculate trends in DKA hospitalization rates and in-hospital case-fatality rates. Overall, age-adjusted DKA hospitalization rates decreased slightly from 2000 to 2009, then reversed direction, steadily increasing from 2009 to 2014 at an average annual rate of 6.3%. In-hospital case-fatality rates declined consistently during the study period from 1.1% to 0.4%. Better understanding the causes of this increasing trend in DKA hospitalizations and decreasing trend in in-hospital case-fatality through further exploration using multiple data sources will facilitate the targeting of prevention efforts.

Diabetes-Related Emergency Medical Service Activations in 23 States, United States 2015.

OBJECTIVE: The use of emergency medical services (EMS) for diabetes-related events is believed to be substantial but has not been quantified nationally despite the diverse acute complications associated with diabetes. We describe diabetes-related EMS activations in 2015 among people of all ages from 23 U.S. states. METHODS: We used data from 23 states that reported ≥95% of their EMS activations to the U.S. National Emergency Medical Services Information System (NEMSIS) in 2015. A diabetes-related EMS activation was defined using coded EMS provider impressions of "diabetes symptoms" and coded complaints recorded by dispatch of "diabetic problem." We described activations by type of location, urbanicity, U.S. Census Division, season, and time of day; and patient-events by age category, race/ethnicity, disposition, and treatment with glucose. Crude and age-adjusted diabetes-related EMS patient-level event rates were calculated for adults ≥18 years of age with diagnosed diabetes using the Behavioral Risk Factor Surveillance System to estimate the population denominator. RESULTS: Of 10,324,031 relevant EMS records, 241,495 (2.3%) were diabetes-related activations, which involved over 235,000 hours of service. Most activations occurred in urban or suburban environ- ments (86.4%), in the home setting (73.5%), and were slightly more frequent in the summer months. Most patients (72.6%) were ≥45 years of age and over one-half (55.4%) were transported to the emergency department. The overall age-adjusted diabetes-related EMS event rate was 33.9 per 1,000 persons with diagnosed diabetes; rates were highest in patients 18-44 years of age, males, and non-Hispanic blacks and varied by U.S. Census Division. CONCLUSIONS: Diabetes results in a substantial burden on EMS resources. Collection of more detailed diabetes complication information in NEMSIS may help facilitate EMS resource planning and prevention strategies.

Association of Diabetes and Tuberculosis Disease among US-Bound Adult Refugees, 2009-2014.

Diabetes is associated with an increased risk for active tuberculosis (TB) disease. We conducted a case-control study and found a significant association between diabetes and TB disease among US-bound refugees. These findings underscore the value of collaborative management of both diseases.

Energy homeostasis in apolipoprotein AIV and cholecystokinin-deficient mice.

Apolipoprotein AIV (ApoAIV) and cholecystokinin (CCK) are well-known satiating signals that are stimulated by fat consumption. Peripheral ApoAIV and CCK interact to prolong satiating signals. In the present study, we hypothesized that ApoAIV and CCK control energy homeostasis in response to high-fat diet feeding. To test this hypothesis, energy homeostasis in ApoAIV and CCK double knockout (ApoAIV/CCK-KO), ApoAIV knockout (ApoAIV-KO), and CCK knockout (CCK-KO) mice were monitored. When animals were maintained on a low-fat diet, ApoAIV/CCK-KO, ApoAIV-KO, and CCK-KO mice had comparable energy intake and expenditure, body weight, fat mass, fat absorption, and plasma parameters relative to the controls. In contrast, these KO mice exhibited impaired lipid transport to epididymal fat pads in response to intraduodenal infusion of dietary lipids. Furthermore, ApoAIV-KO mice had upregulated levels of CCK receptor 2 (CCK2R) in the small intestine while ApoAIV/CCK-KO mice had upregulated levels of CCK2R in the brown adipose tissue. After 20 wk of a high-fat diet, ApoAIV-KO and CCK-KO mice had comparable body weight and fat mass, as well as lower energy expenditure at some time points. However, ApoAIV/CCK-KO mice exhibited reduced body weight and adiposity relative to wild-type mice, despite having normal food intake. Furthermore, ApoAIV/CCK-KO mice displayed normal fat absorption and locomotor activity, as well as enhanced energy expenditure. These observations suggest that mice lacking ApoAIV and CCK have reduced body weight and adiposity, possibly due to impaired lipid transport and elevated energy expenditure.

Evaluation of Measles-Mumps-Rubella Vaccination Among Newly Arrived Refugees.

OBJECTIVES: To assess US availability and use of measles-mumps-rubella (MMR) vaccination documentation for refugees vaccinated overseas. METHODS: We selected 1500 refugee records from 14 states from March 2013 through July 2015 to determine whether overseas vaccination records were available at the US postarrival health assessment and integrated into the Advisory Committee on Immunization Practices schedule. We assessed number of doses, dosing interval, and contraindications. RESULTS: Twelve of 14 (85.7%) states provided data on 1118 (74.5%) refugees. Overseas records for 972 (86.9%) refugees were available, most from the Centers for Disease Control and Prevention's Electronic Disease Notification system (66.9%). Most refugees (829; 85.3%) were assessed appropriately for MMR vaccination; 37 (3.8%) should have received MMR vaccine but did not; 106 (10.9%) did not need the MMR vaccine but were vaccinated. CONCLUSIONS: Overseas documentation was available at most clinics, and MMR vaccinations typically were given when needed. Further collaboration between refugee health clinics and state immunization information systems would improve accessibility of vaccination documentation.

Effectiveness of Monovalent and Pentavalent Rotavirus Vaccines in Guatemala.

BACKGROUND: Concerns remain about lower effectiveness and waning immunity of rotavirus vaccines in resource-poor populations. We assessed vaccine effectiveness against rotavirus in Guatemala, where both the monovalent (RV1; 2-dose series) and pentavalent (RV5; 3-dose series) vaccines were introduced in 2010. METHODS: A case-control evaluation was conducted in 4 hospitals from January 2012 to August 2013. Vaccine status was compared between case patients (children with laboratory-confirmed rotavirus diarrhea) and 2 sets of controls: nondiarrhea "hospital" controls (matched by birth date and site) and nonrotavirus "test-negative" diarrhea controls (adjusted for age, birth month/year, and site). Vaccine effectiveness ([1 - odds ratio of vaccination] × 100%) was computed using logistic regression models. RESULTS: We evaluated 213 case patients, 657 hospital controls, and 334 test-negative controls. Effectiveness of 2-3 doses of a rotavirus vaccine against rotavirus requiring emergency department visit or hospitalization was 74% (95% confidence interval [CI], 58%-84%) with hospital controls, and 52% (95% CI, 26%-69%) with test-negative controls. Using hospital controls, no significant difference in effectiveness was observed between infants 6-11 months (74% [95% CI, 18%-92%]) and children ≥12 months of age (71% [95% CI, 44%-85%]) (P= .85), nor between complete courses of RV1 (63% [95% CI, 23%-82%]) and RV5 (69% [95% CI, 29%-87%]) (P= .96). An uncommon G12P[8] strain, partially heterotypic to strains in both vaccines, was identified in 89% of cases. CONCLUSIONS: RV1 and RV5 were similarly effective against severe rotavirus diarrhea caused by a heterotypic strain in Guatemala. This supports broader implementation of rotavirus vaccination in low-income countries where >90% global deaths from rotavirus occur.

Multistate Outbreak of Respiratory Infections Among Unaccompanied Children, June 2014-July 2014.

BACKGROUND: From January 2014-July 2014, more than 46 000 unaccompanied children (UC) from Central America crossed the US-Mexico border. In June-July, UC aged 9-17 years in 4 shelters and 1 processing center in 4 states were hospitalized with acute respiratory illness. We conducted a multistate investigation to interrupt disease transmission. METHODS: Medical charts were abstracted for hospitalized UC. Nonhospitalized UC with influenza-like illness were interviewed, and nasopharyngeal and oropharyngeal swabs were collected to detect respiratory pathogens. Nasopharyngeal swabs were used to assess pneumococcal colonization in symptomatic and asymptomatic UC. Pneumococcal blood isolates from hospitalized UC and nasopharyngeal isolates were characterized by serotyping and whole-genome sequencing. RESULTS: Among 15 hospitalized UC, 4 (44%) of 9 tested positive for influenza viruses, and 6 (43%) of 14 with blood cultures grew pneumococcus, all serotype 5. Among 48 nonhospitalized children with influenza-like illness, 1 or more respiratory pathogens were identified in 46 (96%). Among 774 nonhospitalized UC, 185 (24%) yielded pneumococcus, and 70 (38%) were serotype 5. UC transferring through the processing center were more likely to be colonized with serotype 5 (odds ratio, 3.8; 95% confidence interval, 2.1-6.9). Analysis of core pneumococcal genomes detected 2 related, yet independent, clusters. No pneumococcus cases were reported after pneumococcal and influenza immunization campaigns. CONCLUSIONS: This respiratory disease outbreak was due to multiple pathogens, including Streptococcus pneumoniae serotype 5 and influenza viruses. Pneumococcal and influenza vaccinations prevented further transmission. Future efforts to prevent similar outbreaks will benefit from use of both vaccines.

Modeling the clinical phenotype of BTK inhibition in the mature murine immune system.

Inhibitors of Bruton's tyrosine kinase (BTK) possess much promise for the treatment of oncologic and autoimmune indications. However, our current knowledge of the role of BTK in immune competence has been gathered in the context of genetic inactivation of btk in both mice and man. Using the novel BTK inhibitor PF-303, we model the clinical phenotype of BTK inhibition by systematically examining the impact of PF-303 on the mature immune system in mice. We implicate BTK in tonic BCR signaling, demonstrate dependence of the T3 B cell subset and IgM surface expression on BTK activity, and find that B1 cells survive and function independently of BTK. Although BTK inhibition does not impact humoral memory survival, Ag-driven clonal expansion of memory B cells and Ab-secreting cell generation are inhibited. These data define the role of BTK in the mature immune system and mechanistically predict the clinical phenotype of chronic BTK inhibition.

Insulin Sensitivity and ß-Cell Function Improve after Gastric Bypass in Severely Obese Adolescents.

OBJECTIVE: To test the hypothesis that insulin secretion and insulin sensitivity would be improved in adolescents after Roux-en-Y gastric bypass (RYGB). STUDY DESIGN: A longitudinal study of 22 adolescents and young adults without diabetes undergoing laparoscopic RYGB (mean age 17.1 ± 1.42 years; range 14.5-20.1; male/female 8/14; Non-Hispanic White/African American 17/5) was conducted. Intravenous glucose tolerance tests were done to obtain insulin sensitivity (insulin sensitivity index), insulin secretion (acute insulin response to glucose ), and the disposition index as primary outcome variables. These variables were compared over the 1 year of observation using linear mixed modeling. RESULTS: In the 1-year following surgery, body mass index fell by 38% from a mean of 61 ± 12.3 to 39 ± 8.0 kg/m(2) (P < .01). Over the year following surgery, fasting glucose and insulin values declined by 54% and 63%, respectively. Insulin sensitivity index increased 300% (P < .01), acute insulin response to glucose decreased 56% (P < .01), leading to a nearly 2-fold increase in the disposition index (P < .01). Consistent with improved ß-cell function, the proinsulin to C-peptide ratio decreased by 21% (P < .01). CONCLUSIONS: RYGB reduced body mass index and improved both insulin sensitivity and ß-cell function in severely obese teens and young adults. These findings demonstrate that RYGB is associated with marked metabolic improvements in obese young people even as significant obesity persists. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00360373.

Selective inhibition of BTK prevents murine lupus and antibody-mediated glomerulonephritis.

Autoantibody production and immune complex deposition within the kidney promote renal disease in patients with lupus nephritis. Thus, therapeutics that inhibit these pathways may be efficacious in the treatment of systemic lupus erythematosus. Bruton's tyrosine kinase (BTK) is a critical signaling component of both BCR and FcR signaling. We sought to assess the efficacy of inhibiting BTK in the development of lupus-like disease, and in this article describe (R)-5-amino-1-(1-cyanopiperidin-3-yl)-3-(4-[2,4-difluorophenoxy]phenyl)-1H-pyrazole-4-carboxamide (PF-06250112), a novel highly selective and potent BTK inhibitor. We demonstrate in vitro that PF-06250112 inhibits both BCR-mediated signaling and proliferation, as well as FcR-mediated activation. To assess the therapeutic impact of BTK inhibition, we treated aged NZBxW_F1 mice with PF-06250112 and demonstrate that PF-06250112 significantly limits the spontaneous accumulation of splenic germinal center B cells and plasma cells. Correspondingly, anti-dsDNA and autoantibody levels were reduced in a dose-dependent manner. Moreover, administration of PF-06250112 prevented the development of proteinuria and improved glomerular pathology scores in all treatment groups. Strikingly, this therapeutic effect could occur with only a modest reduction observed in anti-dsDNA titers, implying a critical role for BTK signaling in disease pathogenesis beyond inhibition of autoantibody production. We subsequently demonstrate that PF-06250112 prevents proteinuria in an FcR-dependent, Ab-mediated model of glomerulonephritis. Importantly, these results highlight that BTK inhibition potently limits the development of glomerulonephritis by impacting both cell- and effector molecule-mediated pathways. These data provide support for evaluating the efficacy of BTK inhibition in systemic lupus erythematosus patients.