BTK inhibition modulates multiple immune cell populations involved in the pathogenesis of immune mediated nephritis.

Lupus nephritis (LN) is a serious end organ complication of systemic lupus erythematosus. Nephrotoxic serum nephritis (NTN) is an inducible model of LN, which utilizes passive transfer of pre-formed nephrotoxic antibodies to initiate disease. In previous studies, we demonstrated that the Bruton's tyrosine kinase inhibitor, BI-BTK-1, prevents the development of nephritis in NTN when treatment was started prior to nephrotoxic serum transfer, and reverses established proteinuria as well. We manipulated the initiation and duration of BI-BTK-1 therapy in NTN to study its delayed therapeutic effects when treatment is given later in the disease course, as well as to further understand what effect BI-BTK-1 is having to prevent initiation of nephritis with early treatment. Early treatment and remission induction each correlated with decreased inflammatory macrophages, CD4+ and CD8+ T cells, and decreased B220+ B cells. Additionally, an increased proportion of resident macrophages within the CD45+ population favored a delay of disease onset and remission induction. We also studied the cellular processes involved in reactivation of nephritis by withdrawing BI-BTK-1 treatment at different time points. Treatment cessation led to either early or later onset of renal flares inversely dependent on the initial duration of BTK inhibition, as assessed by increased proteinuria and BUN levels and worse renal pathology. These flares were associated with an increase in kidney CD45+ infiltrates, including myeloid cell populations. IL-6, CD14, and CCL2 were also increased in mice developing late flares. These analyses point to the role of macrophages as an important contributor to the pathogenesis of immune mediated nephritis, and further support the therapeutic potential of BTK inhibition in this disease and related conditions.

BTK inhibition ameliorates kidney disease in spontaneous lupus nephritis.

Lupus nephritis is a common disease manifestation of SLE, in which immune complex deposition and macrophage activation are important contributors to disease pathogenesis. Bruton's tyrosine kinase (BTK) plays an important role in both B cell and FcgammaR mediated myeloid cell activation. In the current study, we examined the efficacy of BI-BTK-1, a recently described irreversible BTK inhibitor, in the classical NZB × NZW F1 (NZB/W) and MRL/lpr spontaneous mouse models of SLE. NZB/W mice were randomly assigned to a treatment (0.3 mg/kg, 1 mg/kg, 3 mg/kg and 10 mg/kg) or control group and began treatment at 22 weeks of age. The experimental setup was similar in MRL/lpr mice, but with a single treated (10 mg/kg, beginning at 8-9 weeks of age) and control group. A separate experiment was performed in the MRL/lpr strain to assess the ability of BI-BTK-1 to reverse established kidney disease. Early treatment with BI-BTK-1 significantly protected NZB/W and MRL/lpr mice from the development of proteinuria, correlating with significant renal histological protection, decreased anti-DNA titers, and increased survival in both strains. BI-BTK-1 treated mice displayed a significant decrease in nephritis-associated inflammatory mediators (e.g. LCN2 and IL-6) in the kidney, combined with a significant inhibition of immune cell infiltration and accumulation. Importantly, BI-BTK-1 treatment resulted in the reversal of established kidney disease. BTK inhibition significantly reduced total B cell numbers and all B cell subsets (immature, transitional, follicular, marginal zone, and class switched) in the spleen of NZB/W mice. Overall, the significant efficacy of BI-BTK-1 in ameliorating multiple pathological endpoints associated with kidney disease in two distinct murine models of spontaneous lupus nephritis provides a strong rationale for BTK inhibition as a promising treatment approach for lupus nephritis.

Highly selective inhibition of Bruton's tyrosine kinase attenuates skin and brain disease in murine lupus.

BACKGROUND: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that affects different end organs, including skin and brain. We and others have previously shown the importance of macrophages in the pathogenesis of cutaneous and neuropsychiatric lupus. Additionally, autoantibodies produced by autoreactive B cells are thought to play a role in both the skin and central nervous system pathologies associated with SLE. METHODS: We used a novel inhibitor of Bruton's tyrosine kinase (BTK), BI-BTK-1, to target both macrophage and B cell function in the MRL-lpr/lpr murine model of SLE, and examined the effect of treatment on skin and brain disease. RESULTS: We found that treatment with BI-BTK-1 significantly attenuated the lupus associated cutaneous and neuropsychiatric disease phenotypes in MRL/lpr mice. Specifically, BI-BTK-1 treated mice had fewer macroscopic and microscopic skin lesions, reduced cutaneous cellular infiltration, and diminished inflammatory cytokine expression compared to control mice. BTK inhibition also significantly improved cognitive function, and decreased accumulation of T cells, B cells, and macrophages within the central nervous system, specifically the choroid plexus. CONCLUSIONS: Directed therapies may improve the response rate in lupus-driven target organ involvement, and decrease the dangerous side effects associated with global immunosuppression. Overall, our results suggest that inhibition of BTK may be a promising therapeutic option for cutaneous and neuropsychiatric disease associated with SLE.

Therapeutic Blockade of Immune Complex-Mediated Glomerulonephritis by Highly Selective Inhibition of Bruton's Tyrosine Kinase.

Lupus nephritis (LN) is a potentially dangerous end organ pathology that affects upwards of 60% of lupus patients. Bruton's tyrosine kinase (BTK) is important for B cell development, Fc receptor signaling, and macrophage polarization. In this study, we investigated the effects of a novel, highly selective and potent BTK inhibitor, BI-BTK-1, in an inducible model of LN in which mice receive nephrotoxic serum (NTS) containing anti-glomerular antibodies. Mice were treated once daily with vehicle alone or BI-BTK-1, either prophylactically or therapeutically. When compared with control treated mice, NTS-challenged mice treated prophylactically with BI-BTK-1 exhibited significantly attenuated kidney disease, which was dose dependent. BI-BTK-1 treatment resulted in decreased infiltrating IBA-1+ cells, as well as C3 deposition within the kidney. RT-PCR on whole kidney RNA and serum profiling indicated that BTK inhibition significantly decreased levels of LN-relevant inflammatory cytokines and chemokines. Renal RNA expression profiling by RNA-seq revealed that BI-BTK-1 dramatically modulated pathways related to inflammation and glomerular injury. Importantly, when administered therapeutically, BI-BTK-1 reversed established proteinuria and improved renal histopathology. Our results highlight the important role for BTK in the pathogenesis of immune complex-mediated nephritis, and BTK inhibition as a promising therapeutic target for LN.

From idea to implementation: creation of an educational picture book for radiation therapy patients.

Patient education is an integral part of the cancer patient's journey. Radiation therapists strive to provide timely, effective, and evidence-based information on care processes, side effects, and side effect management treatment strategies. Patient satisfaction surveys in health-care settings can guide new interventions and strategies to provide the right education to patients at the right time. Courses offered in adult education and patient education to practicing health-care providers allow for a unique opportunity to look at the current provision of health-care education to patients. This paper explores the development and implementation of a new visual aid for radiation therapy patients in an acute health-care setting with a diversity of languages spoken using principles of adult education.

Fever management practices of neuroscience nurses: national and regional perspectives.

Neuroscience patients with fever may have worse outcomes than those who are afebrile. However, neuroscience nurses who encounter this common problem face a translational gap between patient-outcomes research and bedside practice because there is no current evidence-based standard of care for fever management of the neurologically vulnerable patient. The aim of this study was to determine if there are trends in national practices for fever and hyperthermia management of the neurologically vulnerable patient. A 15-item mailed questionnaire was used to determine national and regional trends in fever and hyperthermia management and decision making by neuroscience nurses. Members of the American Association of Neuroscience Nurses were surveyed (N = 1,225) and returned 328 usable surveys. Fewer than 20% of respondents reported having an explicit fever management protocol in place for neurologic patients, and 12.5% reported having a nonspecific patient protocol available for fever management. Several clear and consistent patterns in interventions for fever and hyperthermia management were seen nationally, including acetaminophen administration at a dose of 650 mg every 4 hours, ice packs, water cooling blankets, and tepid bathing. However, regional differences were seen in intervention choices and initial temperature to treat.

Racial/Ethnic Differences in Dually Diagnosed Anglo and Ethnic Minority Women Receiving Chemical Dependency Treatment.

This article examines racial/ethnic differences in a sample of 51 dually diagnosed women who received chemical dependency treatment. Comparisons are made between Anglo and racial/ethnic minority women at admission to the inpatient treatment program and at follow-up where data are available. Findings from a repeated measures design showed significant decreases in several problem domains for the overall sample. Significant racial/ethnic differences were found only for the other drugs domain. Anglo women reported greater decreases than racial/ethnic minority women in the majority of the domains. Findings suggest continued investigations to inform culturally competent treatment for all dually diagnosed women.

Gender differences in dually-diagnosed clients receiving chemical dependency treatment.

This article considers gender differences among 97 clients with dual diagnoses of severe mental illness and chemical dependency (46 male and 51 female). Comparisons are made at the time of their admission to an inpatient chemical dependency treatment program and at follow-up in cases where data are available. Many of the findings at time of admission are consistent with the few studies that have compared men and women with co-occurring mental and substance use disorders. For example, the women were more likely to have experienced emotional, physical, or sexual abuse, and they reported being charged with fewer types of crimes. Most differences at admission concerned psychiatric problems and family/social relations. Women reported that they were more bothered by their psychiatric symptoms and their family/social relations, but they also reported more happiness and closeness in some relationships. The women also said they had more relatives with alcohol, drug, and especially psychiatric, problems. At follow-up, gender differences in the family/social and psychiatric domains persisted. Findings suggest that men and women with dual diagnoses might benefit from different emphases in treatment programs.