Citations

Objective To identify the clinical and laboratory predictors of clinical improvement in a cohort of myositis patients treated with rituximab. Methods We analyzed data for 195 patients with myositis (75 with adult polymyositis [PM], 72 with adult dermatomyositis [DM], and 48 with juvenile DM) in the Rituximab in Myositis trial. Clinical improvement was defined as 20% improvement in at least 3 of the following 6 core set measures of disease activity: physician's and patient's/parent's global assessment of disease activity, manual muscle testing, physical function, muscle enzymes, and extramuscular disease activity. We analyzed the association of the following baseline variables with improvement: myositis clinical subgroup, demographics, myositis damage, clinical and laboratory parameters, core set measures, rituximab treatment, and myositis autoantibodies (antisynthetase, anti–Mi‐2, anti–signal recognition particle, anti–transcription intermediary factor 1γ [TIF‐1γ], anti‐MJ, other autoantibodies, and no autoantibodies). All measures were univariately assessed for association with improvement using time‐to‐event analyses. A multivariable time‐dependent proportional hazards model was used to evaluate the association of individual predictive factors with improvement. Results In the final multivariable model, the presence of an antisynthetase, primarily anti–Jo‐1 (hazard ratio [HR] 3.08, P < 0.01), anti–Mi‐2 (HR 2.5, P < 0.01), or other autoantibody (HR 1.4, P = 0.14) predicted a shorter time to improvement compared to the absence of autoantibodies. A lower physician's global assessment of damage (HR 2.32, P = 0.02) and juvenile DM (versus adult myositis) (HR 2.45, P = 0.01) also predicted improvement. Unlike autoantibody status, the predictive effect of physician's global assessment of damage and juvenile DM diminished by week 20. Rituximab treatment did not affect these associations. Conclusion Our findings indicate that the presence of antisynthetase and anti–Mi‐2 autoantibodies, juvenile DM subset, and lower disease damage strongly predict clinical improvement in patients with refractory myositis.

AbstractAims and objectivesThe aim of this study was to assess the impact of historical screening compliance with the effectiveness of patient reminder letters on cervical cancer screening rates.MethodUsing population‐based informatics systems, women with no cervical cancer screening in the prior 3 years were identified in two primary care clinics, Mayo Family Clinic Northeast (NE; n = 1613) and Northwest (NW; n = 1088). Patients were divided into two compliance groups: overdue/unknown screening status at study start or previously compliant. The NE Clinic sent reminder letters over a 6 months window to patients eligible for screening at the study start or during the study that were also identified as employees/dependents (E/D). There were 795 intervention (NE Clinic E/D patients) and 1906 control subjects. Using an intent‐to‐treat analysis, differences in screening rates were assessed.ResultsA higher unadjusted screening rate was observed for the E/D group than the non‐E/D group at both sites (32.7 versus 18.2% at NW, P < 0.001; 39.0 versus 14.7% at NE, P < 0.001). For the historically compliant group, unadjusted screening rates were higher for those who received letters (E/D subjects at NE) versus those who did not (E/D subjects at NW; 56.1 versus 44.5%, P = 0.01). No difference was observed between E/D subjects at NE (received letters) and NW (no letters) for the overdue/unknown group (27.4 versus 25.9%, P = 0.62). There was no difference in screening rates for non‐E/D subjects at NE versus at NW (none of whom received letters) for both the compliant (24.2 versus 30.6%, P = 0.18) and the overdue/unknown groups (11.9 versus 13.0%, P = 0.59). Multivariate logistic regression models showed a significant overall effect of E/D status (P = 0.006), compliance group (P < 0.001), and the interaction between clinic site and E/D status (P = 0.04).ConclusionAmong insured women, reminder letters appear to improve cervical cancer screening rates for those with a history of screening compliance. Reminder letters appear insufficient to motivate women if screening is overdue. Further investigation of the cohort of women overdue for screening is needed to develop interventions to successfully target this group.

Acute interstitial nephritis (AIN) is an important and common cause of acute kidney injury, particularly in hospitalized patients. The classic presentation of AIN includes fever, rash, arthralgias, eosinophilia, and acute kidney injury. While renal biopsy is considered the gold standard for diagnosis, the clinical presentation of fever and rash along with laboratory evidence of peripheral blood eosinophilia, eosinophiluria, and low-grade proteinuria strongly suggest the diagnosis. Histologically, interstitial inflammation with interstitial edema and tubulitis is the hallmark of interstitial nephritis. The most common causative factors are drugs, infections, and certain immune-mediated disorders. Discontinuation of the offending agent is considered the mainstay of therapy while the use of corticosteroids to hasten renal recovery may be beneficial. The role of interstitial nephritis in the pathogenesis of chronic kidney disease and end-stage renal disease is increasingly recognized, further emphasizing the importance of its early diagnosis and timely treatment.

SummaryMultiple myeloma, the second most common haematological malignancy in the U.S., is currently incurable. Disruption of the intrinsic apoptotic pathway by BCL2 and MCL1 upregulation is observed in >80% of myeloma cases and is associated with an aggressive clinical course. Remarkably, there is no approved drug with the ability to target BCL2 or MCL1. Thus, we investigated the anti‐tumour effects of a pan‐BCL2 inhibitor, AT‐101, which has high binding specificity for BCL2 and MCL1 in preclinical models of plasma cell cancers (Multiple myeloma and Waldenström macroglobulinaemia). Gene expression and immunoblot analysis of six plasma cell cancer models showed upregulation of BCL2 family members. AT‐101 was able to downregulate BCL2 and MCL1 in all plasma cell cancer models and induced apoptotic cell death in a caspase‐dependent manner by altering mitochondrial membrane permeability. This cytotoxic effect and BCL2 downregulation were further potentiated when AT‐101 was combined with lenalidomide/dexamethasone (LDA). NanoString nCounter mRNA quantification and Ingenuity Pathways Analysis revealed differential changes in the CCNA2, FRZB, FYN, IRF1, PTPN11 genes in LDA‐treated cells. In summary, we describe for the first time the cellular and molecular events associated with the use of AT‐101 in combination with lenalidomide/dexamethasone in preclinical models of plasma cell malignancy.

Abstract Part of the substantial unexplained familial aggregation of breast cancer may be due to interactions between common variants, but few studies have had adequate statistical power to detect interactions of realistic magnitude. We aimed to assess all two-way interactions in breast cancer susceptibility between 70 917 single nucleotide polymorphisms (SNPs) selected primarily based on prior evidence of a marginal effect. Thirty-eight international studies contributed data for 46 450 breast cancer cases and 42 461 controls of European origin as part of a multi-consortium project (COGS). First, SNPs were preselected based on evidence (P &lt; 0.01) of a per-allele main effect, and all two-way combinations of those were evaluated by a per-allele (1 d.f.) test for interaction using logistic regression. Second, all 2.5 billion possible two-SNP combinations were evaluated using Boolean operation-based screening and testing, and SNP pairs with the strongest evidence of interaction (P &lt; 10−4) were selected for more careful assessment by logistic regression. Under the first approach, 3277 SNPs were preselected, but an evaluation of all possible two-SNP combinations (1 d.f.) identified no interactions at P &lt; 10−8. Results from the second analytic approach were consistent with those from the first (P &gt; 10−10). In summary, we observed little evidence of two-way SNP interactions in breast cancer susceptibility, despite the large number of SNPs with potential marginal effects considered and the very large sample size. This finding may have important implications for risk prediction, simplifying the modelling required. Further comprehensive, large-scale genome-wide interaction studies may identify novel interacting loci if the inherent logistic and computational challenges can be overcome.