Abatacept Use Is Associated with Steroid Dose Reduction and Improvement in Fatigue and CD4-Dysregulation in CVID Patients with Interstitial Lung Disease.

BACKGROUND: Interstitial lung disease (ILD) represents a severe clinical manifestation of systemic immune dysregulation in patients with common variable immunodeficiency (CVID). Its treatment often requires systemic immunosuppression beyond corticosteroids. OBJECTIVE: To assess the safety and efficacy of abatacept in patients with CVID and ILD. METHODS: Ten patients with confirmed diagnosis of CVID and ILD were included in a single-center, prospective, open-label, nonrandomized trial. Abatacept was administered subcutaneously at a dose of 125 mg/wk for 12 months. RESULTS: Abatacept was a safe treatment for ILD in CVID except for 1 case of bronchopulmonary aspergillosis. One additional patient terminated the trial prematurely because of recurrent bronchitis. Five of 8 patients treated per protocol benefited from the treatment according to American Thoracic Society/European Respiratory Society criteria. The primary end point of the study was met because single breath diffusing capacity of the lung for carbon monoxide was stable (62.5%) or improved (37.5%) in all patients treated per protocol. Although nodules (71%) and ground-glass opacities (57%) improved in most patients, other computed tomography pathologies were less responsive. Quality of life improved in 87.5% and fatigue in 57% of patients. Abatacept treatment was associated with significant improvement in CD4 T-cell dysregulation, signified by a decrease in serum soluble IL-2 receptor levels and of proliferating Ki67+ CD4 T cells, and a recovery of total lymphocytes, CD4+ T cells, and naive CD4 T cells. CONCLUSIONS: Abatacept may represent a treatment option for CVID-associated ILD. This pilot study demonstrated a good safety profile, steroid-sparing effect, positive immune modulation, and overall positive treatment response especially in quality of life. Larger controlled studies are needed to confirm these findings.

A prospective study on spontaneous fluctuations between diagnostic and non-diagnostic ECGs in Brugada syndrome: implications for correct phenotyping and risk stratification.

AIMS: Fluctuations between the diagnostic ECG pattern and non-diagnostic ECGs in patients with Brugada syndrome are known, but systematic studies are lacking. The purpose of this study was to prospectively evaluate the spontaneous ECG changes between diagnostic and non-diagnostic ECG patterns in patients diagnosed with Brugada syndrome. METHODS AND RESULTS: In 43 patients with Brugada syndrome (27 males; mean age 45+/-11 years), 310 resting ECGs were obtained during a median follow-up of 17.7 months. The ECGs were analysed for the presence of coved type, saddle-back type or no, respectively unspecific, changes. A coved-type ECG pattern with more than 2 mm ST-segment elevation in at least two right precordial leads was defined as diagnostic. The patients were compared for different clinical characteristics with respect to the pattern of fluctuations. Out of a total of 310 ECGs, 102 (33%) revealed a coved type, 91 (29%) a saddle-back type, and 117 (38%) a normal ECG. Fifteen patients (35%) initially presented with a diagnostic coved-type ECG. Fourteen patients (33%) with an initially coved-type ECG exhibited intermittently non-diagnostic ECGs during follow-up. Only one patient (2%) presented constantly with a coved-type ECG. Out of 28 patients (65%) with an initially non-diagnostic ECG, eight (19%) patients developed a diagnostic coved-type ECG during follow-up. Twenty patients (47%) revealed a coved-type ECG during ajmaline challenge, but never had a baseline coved-type ECG recorded. No significant differences were found in gender and clinical characteristics among patients with or without fluctuations between diagnostic and non-diagnostic basal ECGs. The rate of inducible ventricular fibrillation was significantly higher in patients with more than 50% coved-type ECGs than in patients with less than 50% diagnostic ECGs. CONCLUSION: The prevalence of fluctuations between diagnostic and non-diagnostic ECGs in patients with Brugada syndrome is high and may have an implication on the correct phenotyping and on the risk stratification in patients with Brugada syndrome without aborted sudden cardiac death. For correct phenotyping and risk stratification, repetitive ECG recordings seem to be mandatory.

Intravenous drug challenge using flecainide and ajmaline in patients with Brugada syndrome.

OBJECTIVES: The purpose of this study was to compare the effect of intravenous flecainide and ajmaline with respect to their ability to induce or accentuate the typical ECG pattern of Brugada syndrome. BACKGROUND: Brugada syndrome is associated with a high incidence of sudden cardiac death. The typical ECG pattern of ST-segment elevation in the right precordial leads often is concealed, but it can be unmasked with sodium channel blockers such as flecainide and ajmaline. Little is known about the relative effectiveness of these provocative agents in unmasking Brugada syndrome. METHODS: Intravenous pharmacologic challenge with flecainide and ajmaline was performed. Whole-cell patch clamp techniques were used to assess the relative potency of ajmaline and flecainide to inhibit the transient outward current (I(to)). RESULTS: A coved-type ST-segment elevation in the right precordial leads was induced or enhanced in 22 of 22 patients following ajmaline administration. Among the 22 patients, only 15 patients showed positive response to flecainide, resulting in a positive concordance of 68%. Both drugs produced equivalent changes in QRS and PQ intervals, suggesting similar effects on sodium channel current. Whole-cell patch clamp experiments revealed a reduction of the total charge provided by I(to) with an IC(50) of 216 and 15.2 microM for ajmaline and flecainide, respectively. CONCLUSIONS: Our data demonstrate disparate response of Brugada patients to flecainide and ajmaline, with a failure of flecainide in 7 of 22 cases (32%). Greater inhibition of I(to) by flecainide may render it less effective. These observations have important implication for identification of patients at risk for sudden death.