Objective. The herpes zoster (HZ) vaccine is recommended for adults in the US ages ‡60 years who do not have weakened immune systems. It is unclear how the risk of HZ varies according to age and disease conditions in younger patients with autoimmune or inflammatory (AI) diseases. This study was undertaken to evaluate the age-stratified incidence of HZ in patients with AI diseases as compared to older adults for whom the HZ vaccine is currently recommended by the US Centers for Disease Control and Prevention.Methods. Using linked data obtained from patients who were insured by US commercial and government health care plans during the period 2007-2010, 7 cohorts of patients with AI diseases were assembled: systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), rheumatoid arthritis (RA), psoriatic arthritis (PsA), psoriasis (PsO), ankylosing spondylitis (AS), and gout. Two comparator cohorts were also assembled as controls: adult patients with diabetes and adult subjects without AI diseases or diabetic conditions. HZ was identified using diagnostic codes. Age-specific incidence rates (IRs) of HZ were calculated and compared to the IRs of HZ in control subjects ages 61-70 years who were without AI diseases or diabetic conditions.Results. After review of the linked data, the following number of enrollment periods were identified: 8,395 for patients with SLE, 7,916 for patients with IBD, 50,646 for patients with RA, 2,629 for patients with PsA, 4,299 for patients with PsO, 1,019 for patients with AS, 58,934 for patients with gout, 214,631 for control patients with diabetes, and 330,727 for control subjects without AI diseases and diabetic conditions. The respective highest and lowest IRs of HZ during the study were 19.9 per 1,000 person-years in the SLE cohort and 6.8 per 1,000 person-years in the gout cohort, as compared to an IR of 5.3 per 1,000 person-years in control subjects without AI diseases or diabetic conditions. The age-specific IRs of HZ in patients with RA and those with SLE ages ‡40 years were 1.5-2 times greater than those observed in

BackgroundAcute myeloid leukemia (AML) is one of the most common types of adult acute leukemia. Standard chemotherapies can induce complete remission in selected patients; however, a majority of patients eventually relapse and succumb to the disease. Thus, the development of novel therapeutics for AML is urgently needed. Human C-type lectin-like molecule-1 (CLL-1) is a type II transmembrane glycoprotein, and its expression is restricted to myeloid cells and the majority of AML blasts. Moreover, CLL-1 is expressed in leukemia stem cells (LSCs), but absent in hematopoietic stem cells (HSCs), which may provide a potential therapeutic target for AML treatment.MethodsWe tested the expression of CLL-1 antigen on peripheral blood cells and bone marrow cells in healthy donor and AML patients. Then, we developed a chimeric antigen receptor (CAR) containing a CLL1-specific single-chain variable fragment, in combination with CD28, 4-1BB costimulatory domains, and CD3-ζ signaling domain. We further investigate the function of CLL-1 CAR-T cells.ResultsThe CLL-1 CAR-T cells specifically lysed CLL-1+ cell lines as well as primary AML patient samples in vitro. Strong anti-leukemic activity was observed in vivo by using a xenograft model of disseminated AML. Importantly, CLL-1+ myeloid progenitor cells and mature myeloid cells were specifically eliminated by CLL-1 CAR-T cells, while normal HSCs were not targeted due to the lack of CLL-1 expression.ConclusionsCLL-1 CAR-T represents a promising immunotherapy for the treatment of AML.Electronic supplementary materialThe online version of this article (10.1186/s13045-017-0553-5) contains supplementary material, which is available to authorized users.

Objective To study changes in lipid profiles at 24 weeks among early rheumatoid arthritis (RA) patients participating in the Treatment of Early Rheumatoid Arthritis (TEAR) Trial randomized to initiate methotrexate plus etanercept (MTX+ETA), triple therapy (TT) [MTX plus sulfasalazine plus hydroxychloroquine] or aggressively-titrated MTX monotherapy. Methods The TEAR biorepository study had 459 participating patients. Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were measured in serum plasma at 0 and 24 weeks. Results At 24 weeks, there were statistically significant mean increases in cholesterol levels in the MTX + ETA, TT, and MTX monotherapy arms, the observed increases were 31.4, 28.7 and 30 mg/dL in LDL-C; 19.3, 22.3 and 20.6 mg/dL in HDL-C and 56.8, 53 and 57.3 mg/dL values in TC (p < 0.001 all compared to baseline). There was a statistically significant decrease in TC/HDL-C ratio at 24 weeks in all 3 treatment groups from baseline. There was no difference in any lipid changes between the 3 treatment arms. After multivariable adjustment, change in C-reactive protein was associated with change in LDL-C (p=0.03), HDL-C (p=0.09), and TC (p=0.01), but disease activity score in 28-joints was not. Baseline glucocorticoid use was associated with changes in HDL-C (p=0.03) and TC (p=0.02). Conclusion Levels of TC, LDL-C, and HDL-C increased equivalently shortly after initiation of MTX + ETA, TT and MTX monotherapy among early RA patients with active disease participating in a clinical trial. The clinical relevance of short term changes in traditional lipids on cardiovascular outcomes remains to be determined.

IntroductionAdministrative claims data have not commonly been used to study the clinical effectiveness of medications for rheumatoid arthritis (RA) because of the lack of a validated algorithm for this outcome. We created and tested a claims-based algorithm to serve as a proxy for the clinical effectiveness of RA medications.MethodsWe linked Veterans Health Administration (VHA) medical and pharmacy claims for RA patients participating in the longitudinal Department of Veterans Affairs (VA) RA registry (VARA). Among individuals for whom treatment with a new biologic agent or nonbiologic disease-modifying agent in rheumatic disease (DMARD) was being initiated and with registry follow-up at 1 year, VARA and administrative data were used to create a gold standard for the claims-based effectiveness algorithm. The gold standard outcome was low disease activity (LDA) (Disease Activity Score using 28 joint counts (DAS28) ≤ 3.2) or improvement in DAS28 by > 1.2 units at 12 ± 2 months, with high adherence to therapy. The claims-based effectiveness algorithm incorporated biologic dose escalation or switching, addition of new disease-modifying agents, increase in oral glucocorticoid use and dose as well as parenteral glucocorticoid injections.ResultsAmong 1,397 patients, we identified 305 eligible biologic or DMARD treatment episodes in 269 unique individuals. The patients were primarily men (94%) with a mean (± SD) age of 62 ± 10 years. At 1 year, 27% of treatment episodes achieved the effectiveness gold standard. The performance characteristics of the effectiveness algorithm were as follows: positive predictive value, 76% (95% confidence interval (95% CI) = 71% to 81%); negative predictive value, 90% (95% CI = 88% to 92%); sensitivity, 72% (95% CI = 67% to 77%); and specificity, 91% (95% CI = 89% to 93%).ConclusionsAdministrative claims data may be useful in evaluating the effectiveness of medications for RA. Further validation of this effectiveness algorithm will be useful in assessing its generalizability and performance in other populations.

B7-H3 (also known as CD276) is a newly found molecule of B7 family, which may be a promising target for cancer treatment. B7-H3 protein was demonstrated to be expressed in several kinds of tumor tissues including non-small-cell lung cancer (NSCLC) and prostate cancer. Its expression is highly associated with undesirable treatment outcomes and survival time, due to function of the immune checkpoint molecule. It was classified as either a co-stimulatory molecule for T cell activation or the nonimmunological role of regulating signaling pathways. Although there is still no agreed conclusion on the function of B7-H3, it may be a valuable target for cancer therapy. This review aims to provide a comprehensive, up-to-date summary of the advances in B7-H3 targeting approaches in cancer therapy. Although several challenges remain, B7-H3 offers a new therapeutic target with increased efficacy and less toxicity in future cancer treatment.

LKB1/STK11 is a tumor suppressor and a negative regulator of mammalian target of rapamycin signaling. It is inactivated in 30% of lung cancer cell lines but only 5–15% of primary lung adenocarcinomas. There is evidence that homozygous deletion (HD) of chromosome 19p at the LKB locus contributes to the inactivation of the gene in primary human lung cancers. Here, we used several complementary genetic approaches to assess the LKB1 locus in primary non-small cell lung cancers (NSCLCs). We first analyzed 124 NSCLC cases for allelic imbalance using eight microsatellite markers on chromosome 19p, which revealed an overall rate of 65% (80 of 124) loss of heterozygosity (LOH). We next used chromogenic in situ hybridization (CISH) to directly examine the chromosomal status of the LKB1 locus. In all, 65 of 124 LOH tested samples were available for CISH and 58 of those (89%) showed either loss of one copy of chromosome 19p (LOH, 40 of 65 cases, 62%) or both copies (HD 18 of 65 cases, 28%). The occurrence of HD was significantly more frequent in Caucasian (35%) than in African-American patients (6%) (P=0.04). A total of 62 of 124 samples with LOH at one or both markers immediately flanking the LKB1 gene were further analyzed by directly sequencing the complete coding region, which identified 7 of 62 (11%) tumors with somatic mutations in the gene. Jointly, our data identified total inactivation of the LKB1 gene by either HD or LOH with somatic mutation in 39% of tested samples, whereas loss of chromosome 19p region by HD or LOH at the LKB1 region occured in 90% of NSCLC.

Background Simplified measures to quantify rheumatoid arthritis (RA) disease activity are increasingly used. The minimally clinically important differences (MCID) for some measures, such as the clinical disease activity index (CDAI), have not been well-defined in real-world clinic settings, especially for early RA patients with low/moderate disease activity. Methods Data from Canadian Early Arthritis Cohort patients were used to examine absolute change in CDAI in the first year after enrollment, stratified by disease activity. MCID cutpoints were derived to optimize the sum of sensitivity and specificity versus the gold standard of patient self-reported improvement or worsening. Specificity, positive predictive value and negative predictive values were calculated against patient self-reported improvement (gold standard) and for change in pain, HAQ and DAS28 improvement. Discrimination was examined using area under receiver operator curves (ROC). Similar methods were used to evaluate MCIDs for worsening for patients who achieved low disease activity. Results A total of 578 patients (mean (SD) age 54.1 (15.3) years; 75% women, median (IQR) disease duration 5.3 (3.3, 8.0) months) contributed 1169 visit pairs to the improvement analysis. The MCID cutpoints for improvement were 12 (patients starting in high disease activity, CDAI>22), 6 (moderate, CDAI 10–22), and 1 (low disease activity, CDAI <10). Performance characteristics were acceptable using these cutpoints for pain, HAQ, and DAS28. The MCID for CDAI worsening among patients who achieved low disease activity was 2 units. Conclusions These minimally important absolute differences in CDAI can be used to evaluate improvement and worsening and increase the utility of CDAI in clinical practice.

Background The comparative risk of infection associated with non anti-TNF biologics are not well established. Our objective was to compare risk for hospitalized infections between anti-TNF and non-anti-TNF biologics in U.S. veterans with rheumatoid arthritis (RA). Methods Using 1998–2011 data from the U.S. Veteran’s Health Administration, we studied RA patients initiating rituximab, abatacept or anti-TNF therapy.. Exposure was based upon days supplied (injections) or usual dosing intervals (infusions). Treatment episodes were defined as new biologic use. Hazard ratios (HR, 95% CI) for hospitalization for a bacterial infection were estimated from Cox proportional hazards models, adjusting for potential confounders. Results Among 3152 unique RA patients contributing 4158 biologic treatment episodes to rituximab (n=596), abatacept (n=451), and anti-TNF (n−3111); patient mean age was 60 years, 87% were male. The most common infections were pneumonia(37%), skin/soft tissue(22%), urinary tract(9%), and bacteremia/sepsis(7%). Hospitalized infection rates/100 person-years (95% CI) were 4.4 (3.1, 6.4) for rituximab, 2.8 (1.7, 4.7) for abatacept and 3.0 (2.5, 3.5) for anti-TNF. Compared to etanercept, the adjusted rate of hospitalized infection was not different for adalimumab (HR 1.4, 0.9–2.2), abatacept (HR 1.1, 0.6–2.1), or rituximab (HR 1.4, 0.8–2.6) although was increased for infliximab (HR 2.3, 1.3–4.0). Infection risk was greater for those taking prednisone >7.5mg/day (HR=1.8, 1.3–2.7) and in the highest quartile of C-reactive protein (HR=2.3, 1.4–3.8) and ESR rate (HR= 4., 2.3–7.2)) compared to the lowest quartile. Conclusions In older, predominantly male US veterans with RA, the risk of hospitalized bacterial infections associated with rituximab or abatacept was similar to etanercept.