The Type I Interferon Signature Reflects Multiple Phenotypic and Activity Measures in Dermatomyositis.

OBJECTIVE: The type 1 interferon (IFN) pathway is up-regulated in dermatomyositis (DM). We sought to define how organ-specific disease activity as well as autoantibodies and other clinical factors are independently associated with systemic type I IFN activity in adult patients with DM. METHODS: RNA sequencing was performed on 355 whole blood samples collected from 202 well-phenotyped DM patients followed up during the course of their clinical care. A previously defined 13-gene type I IFN score was modeled as a function of demographic, serologic, and clinical variables using both cross-sectional and longitudinal data. RESULTS: The pattern of type I IFN-driven transcriptional response was stereotyped across samples with a sequential modular activation pattern strikingly similar to systemic lupus erythematosus. The median type I IFN score was higher or lower in patients with anti-melanoma differentiation-associated protein 5 (anti-MDA-5) or anti-Mi-2 antibodies, respectively, compared to patients without these antibodies. Absolute type I IFN score was independently associated with muscle and skin disease activity, interstitial lung disease, and anti-MDA-5 antibodies. Changes in the type I IFN score over time were significantly associated with changes in skin or muscle disease activity. Stratified analysis accounting for heterogeneity in organ involvement and antibody class revealed high correlation between changes in the type I IFN score and skin disease activity (Spearman's ρ = 0.84-0.95). CONCLUSION: The type I IFN score is independently associated with skin and muscle disease activity as well as certain clinical and serologic features in DM. Accounting for the effect of muscle disease and anti-MDA-5 status revealed that the type I IFN score is strongly correlated with skin disease activity, providing support for type I IFN blockade as a therapeutic strategy for DM.

Growth differentiation factor 15 neutralization does not impact anorexia or survival in lipopolysaccharide-induced inflammation.

Growth differentiation factor 15 (GDF15) causes anorexia and weight loss in animal models, and higher circulating levels are associated with cachexia and reduced survival in cancer and other chronic diseases such as sepsis. To investigate the role of sepsis-induced GDF15, we examined whether GDF15 neutralization via a validated and highly potent monoclonal antibody, mAB2, modulates lipopolysaccharide (LPS)-induced anorexia, weight loss, and mortality in rodents. LPS injection transiently increased circulating GDF15 in wild-type mice, decreased food intake and body weight, and increased illness behavior and mortality at a high dose. GDF15 neutralization with mAB2 did not prevent or exacerbate any of the effects of LPS. Similarly, in GDF15 knockout mice, the LPS effect on appetite and survival was comparable with that observed in wild-type controls. Therefore, effective inhibition of circulating active GDF15 via an antibody or via gene knockout demonstrated that survival in the LPS acute inflammation model was independent of GDF15.

GDF-15 Neutralization Alleviates Platinum-Based Chemotherapy-Induced Emesis, Anorexia, and Weight Loss in Mice and Nonhuman Primates.

Platinum-based cancer therapy is restricted by dose-limiting side effects and is associated with elevation of growth differentiation factor 15 (GDF-15). But whether this elevation contributes to such side effects has been unclear. Here, we explored the effects of GDF-15 blockade on platinum-based chemotherapy-induced emesis, anorexia, and weight loss in mice and/or nonhuman primate models. We found that circulating GDF-15 is higher in subjects with cancer receiving platinum-based chemotherapy and is positively associated with weight loss in colorectal cancer (NCT00609622). Further, chemotherapy agents associated with high clinical emetic score induce circulating GDF-15 and weight loss in mice. Platinum-based treatment-induced anorexia and weight loss are attenuated in GDF-15 knockout mice, while GDF-15 neutralization with the monoclonal antibody mAB1 improves survival. In nonhuman primates, mAB1 treatment attenuates anorexia and emesis. These results suggest that GDF-15 neutralization is a potential therapeutic approach to alleviate chemotherapy-induced side effects and improve the quality of life.

Complete Malleus Removal for Cholesteatoma: A Multivariate Analysis of Ossiculoplasty Success and Residual Disease.

OBJECTIVE: Determine the effect of complete malleus removal during canal wall up tympanomastoidectomy for cholesteatoma on ossiculoplasty success and rate of residual cholesteatoma. METHODS: We reviewed the operative, audiogram, and clinical reports of patients who underwent canal wall up tympanomastoidectomy for cholesteatoma between 2009 and 2016 at a tertiary academic medical center with at least 8 months of follow-up after surgery. To control for extent of disease, we independently catalogued the subsites of the middle ear and mastoid that cholesteatoma involved from each operation. We performed multivariate logistic regression to determine the independent effect of complete removal of the malleus on the rate of residual disease and success of ossiculoplasty. RESULTS: One hundred eighty surgeries were included in the analysis. For ossiculoplasty success, the adjusted odds ratio of complete malleus removal was 1.7 (95% CI, 0.43-7.0, P = .43), which was not statistically significant. For residual disease, the adjusted odds ratio of complete malleus removal versus not was 0.29 (95% CI, 0.074-1.1, P = .076), which approached but did not meet statistical significance. CONCLUSION: Though complete malleus removal does not independently decrease the rate of residual cholesteatoma, it may be a safe technique as it did not compromise ossiculoplasty success.

Reduced serum myostatin concentrations associated with genetic muscle disease progression.

Myostatin is a highly conserved protein secreted primarily from skeletal muscle that can potently suppress muscle growth. This ability to regulate skeletal muscle mass has sparked intense interest in the development of anti-myostatin therapies for a wide array of muscle disorders including sarcopenia, cachexia and genetic neuromuscular diseases. While a number of studies have examined the circulating myostatin concentrations in healthy and sarcopenic populations, very little data are available from inherited muscle disease patients. Here, we have measured the myostatin concentration in serum from seven genetic neuromuscular disorder patient populations using immunoaffinity LC-MS/MS. Average serum concentrations of myostatin in all seven muscle disease patient groups were significantly less than those measured in healthy controls. Furthermore, circulating myostatin concentrations correlated with clinical measures of disease progression for five of the muscle disease patient populations. These findings greatly expand the understanding of myostatin in neuromuscular disease and suggest its potential utility as a biomarker of disease progression.

Peginterferon Beta-1a Shows Antitumor Activity as a Single Agent and Enhances Efficacy of Standard of Care Cancer Therapeutics in Human Melanoma, Breast, Renal, and Colon Xenograft Models.

Because of its tumor-suppressive effect, interferon-based therapy has been used for the treatment of melanoma. However, limited data are available regarding the antitumor effects of pegylated interferons, either alone or in combination with approved anticancer drugs. We report that treatment of human WM-266-4 melanoma cells with peginterferon beta-1a induced apoptotic markers. Additionally, peginterferon beta-1a significantly inhibited the growth of human SK-MEL-1, A-375, and WM-266-4 melanoma xenografts established in immunocompromised mice. Peginterferon beta-1a regressed large, established WM-266-4 xenografts in nude mice. Treatment of SK-MEL-1 tumor-bearing mice with a combination of peginterferon beta-1a and the MEK inhibitor PD325901 ((R)-N-(2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzamide) significantly improved tumor growth inhibition compared with either agent alone. Examination of the antitumor activity of peginterferon beta-1a in combination with approved anticancer drugs in breast and renal carcinomas revealed improved antitumor activity in these preclinical xenograft models, as did the combination of peginterferon beta-1a and bevacizumab in a colon carcinoma xenograft model.

BG9719 (CVT-124), an A1 adenosine receptor antagonist, protects against the decline in renal function observed with diuretic therapy.

BACKGROUND: Adenosine may adversely affect renal function via its effects on renal arterioles and tubuloglomerular feedback, but effects of adenosine blockade in humans receiving furosemide and ACE inhibitors is unknown. METHODS AND RESULTS: This was a randomized, double-blind, ascending-dose, crossover study evaluating 3 doses of BG9719 in 63 patients with congestive heart failure. Patients received placebo or 1 of 3 doses of BG9719 on 1 day and the same medication plus furosemide on a separate day. Renal function and electrolyte and water excretion were assessed. BG9719 alone caused an increase in urine output and sodium excretion (P<0.05). Although administration of furosemide alone caused a large diuresis, addition of BG9719 to furosemide increased diuresis, which was significant at the 0.75-microg/mL concentration. BG9719 alone improved glomerular filtration rate (GFR) at the 2 lower doses. Furosemide alone caused a decline in GFR. When BG9719 was added to furosemide, however, creatinine clearance remained at baseline at the 2 lower doses. CONCLUSIONS: In patients with congestive heart failure on standard therapy, including ACE inhibitors, BG9719 increased both urine output and GFR. In these same patients, furosemide increased urine output at the expense of decreased GFR. When BG9719 was given in addition to furosemide, urine volume additionally increased and there was no deterioration in GFR. A1 adenosine antagonism might preserve renal function while simultaneously promoting natriuresis during treatment for heart failure.