Baricitinib in patients with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids: results from two randomized monotherapy phase III trials.

BACKGROUND: Baricitinib, an oral selective Janus kinase 1 and 2 inhibitor, effectively reduced atopic dermatitis (AD) severity in a phase II study with concomitant topical corticosteroids. OBJECTIVES: To evaluate the efficacy and safety of baricitinib in patients with moderate-to-severe AD who had an inadequate response to topical therapies. METHODS: In two independent, multicentre, double-blind, phase III monotherapy trials, BREEZE-AD1 and BREEZE-AD2, adults with moderate-to-severe AD were randomized 2 : 1 : 1 : 1 to once-daily placebo, baricitinib 1 mg, 2 mg, or 4 mg for 16 weeks. RESULTS: At week 16, more patients achieved the primary end point of Validated Investigator's Global Assessment of AD (0, 1) on baricitinib 4 mg and 2 mg compared with placebo in BREEZE-AD1 [N = 624; baricitinib 4 mg 16·8% (P < 0·001), 2 mg 11·4% (P < 0·05), 1 mg 11·8% (P < 0·05), placebo 4·8%], and BREEZE-AD2 [N = 615; baricitinib 4 mg 13·8% (P = 0·001), 2 mg 10·6% (P < 0·05), 1 mg 8·8% (P = 0·085), placebo 4·5%]. Improvement in itch was achieved as early as week 1 for 4 mg and week 2 for 2 mg. Improvements in night-time awakenings, skin pain and quality-of-life measures were observed by week 1 for both 4 mg and 2 mg (P ≤ 0·05, all comparisons). The most common adverse events in patients treated with baricitinib were nasopharyngitis and headache. No cardiovascular events, venous thromboembolism, gastrointestinal perforation, significant haematological changes, or death were observed with any baricitinib dosage. CONCLUSIONS: Baricitinib improved clinical signs and symptoms in patients with moderate-to-severe AD within 16 weeks of treatment and induced rapid reduction of itch. The safety profile remained consistent with prior findings from baricitinib clinical development in AD, with no new safety concerns.

A randomized phase 2b trial of baricitinib, an oral Janus kinase (JAK) 1/JAK2 inhibitor, in patients with moderate-to-severe psoriasis.

BACKGROUND: Plaque psoriasis is a chronic and often debilitating skin disorder and proinflammatory cytokines are known to play a key role in the disease process. OBJECTIVES: To evaluate the safety and efficacy of baricitinib, an oral Janus kinase (JAK) 1/JAK2 inhibitor, in patients with moderate-to-severe psoriasis in a randomized, double-blind, placebo-controlled, dose-ranging phase 2b study. METHODS: Patients were randomized (n = 271) to receive placebo or oral baricitinib at 2, 4, 8 or 10 mg once daily for 12 weeks (Part A). Dose adjustment for 12 additional weeks was based on percentage improvement in the Psoriasis Area and Severity Index (PASI) score. The primary end point was Psoriasis Area and Severity Index (PASI) 75% (PASI-75) at 12 weeks for North American patients (n = 238); secondary end points were safety and efficacy measures in the entire population. RESULTS: At week 12, more North American patients in the 8-mg (43%) and 10-mg (54%) baricitinib groups than in placebo group (17%; P < 0·05) achieved PASI-75. All baricitinib-treated groups had greater mean changes from baseline in their PASI scores (P < 0·05) at 12 weeks and (except 2 mg) had higher rates of PASI-50 than the placebo group; statistically significant PASI-90 responses were achieved in the 8-mg and 10-mg groups at 8 and 12 weeks. More than 81% of PASI-75 responders maintained their scores through 24 weeks. During Part A, study discontinuations due to adverse events (AEs) were 0%, 0%, 2·8%, 6·3% and 5·8% and treatment-emergent AE rates were 44%, 50%, 47%, 58% and 64% for placebo and 2-, 4-, 8- and 10-mg baricitinib groups, respectively. No opportunistic infections were observed in any treatment group. Dose-dependent changes in laboratory values were observed. CONCLUSIONS: Patients with moderate-to-severe psoriasis treated with baricitinib for 12 weeks achieved significant improvements in PASI-75.

Beyond single-marker analyses: mining whole genome scans for insights into treatment responses in severe sepsis.

Management of severe sepsis, an acute illness with high morbidity and mortality, suffers from the lack of effective biomarkers and largely empirical predictions of disease progression and therapeutic responses. We conducted a genome-wide association study using a large randomized clinical trial cohort to discover genetic biomarkers of response to therapy and prognosis utilizing novel approaches, including combination markers, to overcome limitations of single-marker analyses. Sepsis prognostic models were dominated by clinical variables with genetic markers less informative. In contrast, evidence for gene-gene interactions were identified for sepsis treatment responses with genetic biomarkers dominating models for predicting therapeutic responses, yielding candidates for replication in other cohorts.

Do established prognostic factors explain the different mortality rates in ICU septic patients around the world?

BACKGROUND: The aim of this paper was to clarify if previously established prognostic factors explain the different mortality rates observed in ICU septic patients around the world. METHODS: This is a sub-study from the PROGRESS study, which was an international, prospective, observational registry of ICU patients with severe sepsis. For this study we included 10930 patients from 24 countries that enrolled more than 100 patients in the PROGRESS. The effect of potential prognostic factors on in-hospital mortality was examined using univariate and multivariate logistic regression. The complete set of data was available for 7022 patients, who were considered in the multivariate analysis. Countries were classified according to country income, development status, and in-hospital mortality terciles. The relationship between countries' characteristics and in-hospital mortality was evaluated using linear regression. RESULTS: Mean in-hospital mortality was 49.2%. Severe sepsis in-hospital mortality varied widely in different countries, ranging from 30.6% in New Zealand to 80.4% in Algeria. Classification as developed or developing country was not associated with in-hospital mortality (P=0.16), nor were levels of gross national product per capita (P=0.15). Patients in the group of countries with higher in-hospital mortality had a crude OR for in-hospital death of 2.8 (95% CI 2.5-3.1) in comparison to those in the lower risk group. After adjustments were made for all other independent variables, the OR changed to 2.9 (95% CI 2.5-3.3). CONCLUSION: Severe sepsis mortality varies widely in different countries. All known markers of disease severity and prognosis do not fully explain the international differences in mortality. Country income does not explain this disparity either. Further studies should be developed to verify if other organizational or structural factors account for disparities in patient care and outcomes.

Promoting Global Research Excellence in Severe Sepsis (PROGRESS): lessons from an international sepsis registry.

BACKGROUND: The PROGRESS Registry (Promoting Global Research Excellence in Severe Sepsis) was designed to provide comparative data reflecting everyday clinical practice, thereby allowing participating institutions to explore and benchmark medical interventions in severe sepsis. MATERIALS AND METHODS: PROGRESS was an international, noninterventional, prospective, observational registry collecting data that describe the management and outcomes of severe sepsis patients in intensive care units (ICUs). Patients were enrolled who had been diagnosed with severe sepsis (suspected or proven infection and >or= 1 acute sepsis-induced organ dysfunction) at the participating institutions, where de-identified data were entered directly into a secured website. PROGRESS was governed by an independent international medical advisory board. RESULTS: PROGRESS took place in 276 ICUs in 37 countries, and 12,881 patients were identified as having severe sepsis. There was considerable variation among countries in enrollment levels, provision of standard treatment and supportive therapies, and ICU and hospital outcomes. Eight countries accounted for 65.2% of the enrolled patients. Males (59.3%) and Caucasian (48.6%) patients predominated the patient cohort. Diagnosis of severe sepsis was prior to ICU admission in 45.7% of patients, at ICU admission in 29.1% of patients, and after ICU admission in the remainder. Globally, ICU and hospital mortality rates were 39.2% and 49.6%, respectively. The mean length of ICU and hospital stay was 14.6 days and 28.2 days, respectively. CONCLUSIONS: The PROGRESS international sepsis registry demonstrates that a large web-based sepsis registry is feasible. Wide variations in outcomes and use of sepsis therapies were observed between countries. These results also suggest that additional opportunities exist across countries to improve severe sepsis outcomes.

Severe hypoglycaemia in patients with type 1 diabetes and impaired awareness of hypoglycaemia: a comparative study of insulin lispro and regular human insulin.

OBJECTIVE: To assess the potential of insulin lispro to limit the frequency of severe hypoglycaemia without compromising glycaemic control in a cohort of patients with type 1 diabetes who are at a high risk of severe hypoglycemia. Research design and methods An open-label, randomised, 12-month comparative crossover study of insulin lispro and regular human insulin was performed in 33 patients with type 1 diabetes with impaired hypoglycaemia awareness. The efficacy of each treatment was evaluated by glycaemic control (HbA(1c)), eight-point home blood glucose profiles, and the frequency and severity of hypoglycaemic episodes and quality of life. RESULTS: Eighteen (55%) patients experienced one or more episodes of severe hypoglycaemia in the 48 weeks of study. There was a trend to a lower incidence of severe hypoglycaemia during treatment with insulin lispro in comparison with regular human insulin (55 vs 84 episodes, p=0.087). This resulted principally from a 47% lower incidence of nocturnal severe hypoglycaemia with insulin lispro (25 vs 47 episodes, p=0.11). The lower frequency of severe hypoglycaemia associated with insulin lispro was not explained by differences in glycated haemoglobin between insulin treatments (HbA(1c) 9.1% insulin lispro vs 9.3% regular human insulin). CONCLUSIONS: In individuals with type 1 diabetes, who have impaired awareness of hypoglycaemia, treatment with insulin lispro may be associated with a lower incidence of severe hypoglycaemia manifested predominantly through less frequent nocturnal episodes. Insulin lispro may have a beneficial role in the management of patients with diabetes at risk of severe hypoglycaemia, although a larger study is required to confirm these findings.

The action profile of lispro is not blunted by mixing in the syringe with NPH insulin.

OBJECTIVE: To assess the effect of mixing the insulin analog lispro (Humalog) with NPH (Humulin I) before injection on lispro's fast, short action profile. RESEARCH DESIGN AND METHODS: A total of 12 healthy volunteers received subcutaneous abdominal injections of 0.1 U/kg regular insulin and 0.2 U/kg NPH insulin as follows: lispro and NPH injected separately (treatment group A), lispro and NPH mixed in the syringe up to 2 min before single injection (treatment group B), and human regular insulin and NPH mixed and injected as in group B (treatment group C), on separate occasions, in random order. Plasma glucose was maintained for 12 h by intravenous 20% glucose. Pharmacokinetic and pharmacodynamic parameters were compared by analysis of variance for repeated measures. RESULTS: Peak plasma insulin levels (2.6 +/- 0.8 vs. 2.2 +/- 0.6 vs. 1.9 +/- 0.6 ng/ml, P = 0.075), total glucose infused (121.5 +/- 32.8 vs. 135.0 +/- 49.0 vs. 117.3 +/- 39.9 mg.kg-1.min-1, P = 0.53), and maximum glucose infusion rate (GIRmax) (8.3 +/- 0.9 vs. 8.0 +/- 1.7 vs. 7.1 +/- 2.4 mg.kg-1.min-1, P = 0.65) were not significantly different between treatments. The times until peak insulin concentrations were similar in treatment groups A and B, but significantly shorter than in treatment group C (0.9 +/- 0.3 and 1.2 +/- 0.2 vs. 2.0 +/- 0.4 h, respectively, P = 0.042). The times until GIRmax were also not different (113.9 +/- 41 and 122.0 +/- 45 vs. 209.0 +/- 51.3 min, respectively, P = 0.002). The glucose infusion rate (GIR) then fell to 50% GIRmax more quickly in treatment groups A and B than in treatment group C (239.9 +/- 40.5 vs. 292.4 +/- 133.3 vs. 399.5 +/- 78.3, respectively, P = 0.005). CONCLUSIONS: The action profile of lispro is not attenuated by mixing lispro with NPH in the syringe immediately before injection. The advantages are available to those individuals who need to combine types of insulin before injection to achieve optimal diabetes control.

Lymphedema: results of surgical treatment in 64 patients (1936-1964).

Patients with peripheral lymphedema are usually treated without operation. In some, however, operations are required in order to reduce swelling, ensure comfort, and improve function and appearance. Because new surgical approaches are available for the treatment of peripheral lymphedema, we reviewed our previous operative experiences for these conditions at the Mayo Clinic to provide a reference to which the newer procedures may be compared. Sixty-four patients underwent operation for peripheral lymphedema between 1936 and 1964. Follow-up information was obtained on 56 patients. Seventeen patients required three procedures to alleviate the swelling in an extremity. Morphologic aspects of the excised tissue were also evaluated in these cases. Results were considered excellent in 13, good in 22, fair in 8, and poor in 13. Complications of operation consisted primarily of wound infections, hematomas, and necrosis of skin flaps.

Recurrent anterior dislocation of the shoulder. Long-term follow-up of the Putti-Platt and Bankart procedures.

Follow-up of 176 patients among 223 who underwent 232 repairs for recurrent shoulder dislocation (average follow-up, 10.2 years) revealed a recurrence rate of 11%. Among the twenty with recurrence, important factors were youth, athletic activity, inadequate immobilization, a history of contralateral dislocation, and a family history of shoulder dislocation. Redislocation occurred two years or more after operation in seven of the twenty patients with recurrence. Surgical repair permitted good function without significant pain in most cases.