A single-blinded trial of methotrexate versus azathioprine as steroid-sparing agents in generalized myasthenia gravis

<p>Abstract</p> <p>Background</p> <p>Long-term immunosuppression is often required in myasthenia gravis (MG). There are no published trials using methotrexate (MTX) in MG. The steroid-sparing efficacy of azathioprine (AZA) has been demonstrated after 18-months of starting therapy. However, AZA is considered expensive in Africa. We evaluated the steroid-sparing efficacy of MTX (17.5 mg weekly) compared with AZA (2.5 mg/kg daily) in subjects recently diagnosed with generalized MG by assessing their average monthly prednisone requirements.</p> <p>Methods</p> <p>The primary outcome was the average daily prednisone requirement by month between the two groups. Prednisone was given at the lowest dose to manage MG symptoms and adjusted as required according to protocol. Single-blinded assessments were performed 3-monthly for 2-years to determine the quantitative MG score and the MG activities of daily living score in order to determine those with minimal manifestations of MG.</p> <p>Results</p> <p>Thirty-one subjects (AZA n = 15; MTX n = 16) satisfied the inclusion criteria but only 24 were randomized. Baseline characteristics were similar. There was no difference between the AZA- and MTX-groups in respect of prednisone dosing (apart from months 10 and 12), in quantitative MG Score improvement, proportions in sustained remission, frequencies of MG relapses, or adverse reactions and/or withdrawals. The MTX-group received lower prednisone doses between month 10 (p = 0.047) and month 12 (p = 0.039). At month 12 the prednisone dose per kilogram bodyweight in the MTX-group (0.15 mg/kg) was half that of the AZA-group (0.31 mg/kg)(p = 0.019).</p> <p>Conclusions</p> <p>This study provides evidence that in patients with generalized MG methotrexate is an effective steroid-sparing agent 10 months after treatment initiation. Our data suggests that in generalized MG methotrexate has similar efficacy and tolerability to azathioprine and may be the drug of choice in financially constrained health systems.</p> <p>Trial registration</p> <p>SANCTR:DOH-27-0411-2436</p

On the study of extremes with dependent random right-censoring

The study of extremes in missing data frameworks is a recent developing field. In particular, the randomly right-censored case has been receiving a fair amount of attention in the last decade. All studies on this topic, however, essentially work under the usual assumption that the variable of interest and the censoring variable are independent. Furthermore, a frequent characteristic of estimation procedures developed so far is their crucial reliance on particular properties of the asymptotic behaviour of the response variable Z (that is, the minimum between time-to-event and time-to-censoring) and of the probability of censoring in the right tail of Z. In this paper, we focus instead on elucidating this asymptotic behaviour in the dependent censoring case, and, more precisely, when the structure of the dependent censoring mechanism is given by an extreme value copula. We then draw a number of consequences of our results, related to the asymptotic behaviour, in this dependent context, of a number of estimators of the extreme value index of the random variable of interest that were introduced in the literature under the assumption of independent censoring, and we discuss more generally the implications of our results on the inference of the extremes of this variable

Effect of oral digoxin in high-risk heart failure patients: a pre-specified subgroup analysis of the DIG trial

AIMS: In the Digitalis Investigation Group (DIG) trial, digoxin reduced mortality or hospitalization due to heart failure (HF) in several pre-specified high-risk subgroups of HF patients, but data on protocol-specified 2-year outcomes were not presented. In the current study, we examined the effect of digoxin on HF death or HF hospitalization and all-cause death or all-cause hospitalization in high-risk subgroups during the protocol-specified 2 years of post-randomization follow-up. METHODS AND RESULTS: In the DIG trial, 6800 ambulatory patients with chronic HF, normal sinus rhythm, and LVEF ≤45% (mean age 64 years, 26% women, 17% non-whites) were randomized to receive digoxin or placebo. The three high-risk groups were defined as NYHA class III-IV symptoms (n = 2223), LVEF 55% (n = 2345). In all three high-risk subgroups, compared with patients in the placebo group, those in the digoxin group had a significant reduction in the risk of the 2-year composite endpoint of HF mortality or HF hospitalization: NYHA III-IV [hazard ratio (HR) 0.65; 95% confidence interval (CI) 0.57-0.75; P 55% (HR 0.65; 95% CI 0.57-0.75; P 55% were 0.88 (0.80-0.97; P = 0.012), 0.84 (0.76-0.93; P = 0.001), and 0.85 (0.77-0.94; P = 0.002), respectively. CONCLUSIONS: Digoxin improves outcomes in chronic HF patients with NYHA class III-IV, LVEF 55%, and should be considered in these patients

A propensity-matched study of the effect of diabetes on the natural history of heart failure: variations by sex and age

Poor prognosis in heart failure (HF) patients with diabetes is often attributed to increased co-morbidity and advanced disease. Further, this effect may be worse in women