Efficacy and Safety of Mepolizumab in the Management of Severe Eosinophilic Asthma: A Systematic Review.

Severe eosinophilic asthma (SEA) is characterized by persistent airway inflammation and frequent exacerbations despite standard treatments. Mepolizumab, a monoclonal antibody that reduces eosinophil levels by targeting interleukin-5, has emerged as an add-on therapy for patients with SEA. This systematic review evaluated mepolizumab's efficacy and safety for treating SEA. A comprehensive literature search was conducted across major databases. Thirty-two studies with over 6,000 patients were included, comprising randomized controlled trials, open-label extensions, and real-world observational analyses. Study quality and risk of bias were assessed using standard tools. Meta-analysis was deemed inappropriate due to heterogeneity. Instead, a narrative synthesis was performed. Mepolizumab significantly reduced exacerbation rates by around 50% and improved symptoms and lung function compared to placebo in pivotal trials. Long-term open-label studies showed sustained reductions in exacerbations and stable lung function for up to 4.5 years. Real-world data demonstrated consistent 50%-90% exacerbation decreases across diverse patient populations over 6-24 months. Mepolizumab exhibited an acceptable safety profile, with mild injection site reactions and headaches as most common adverse events. While specific subgroups may show enhanced responses, mepolizumab displayed broad efficacy regardless of patient demographics or phenotypes. The extensive evidence provides robust support for mepolizumab as an efficacious and safe add-on treatment option for patients with severe, refractory eosinophilic asthma. Further high-quality comparative effectiveness research is warranted to optimize patient selection and positioning among emerging biologics.

Follow-up of soluble interleukin-2 receptor levels after thymectomy in patients with myasthenia gravis.

Soluble interleukin-2 receptor (sIL-2R) levels were followed up after thymectomy by a quantitative immunoradiometric assay in 59 patients with myasthenia gravis (MG). Increased levels of sIL-2R were found in 30.5% of the patients before thymectomy. Serum levels were significantly higher in severely affected patients. Sequential sampling after thymectomy indicated a significant and progressive decline of sIL-2R levels within 2 years after surgery, which was well associated with clinical improvement or remission. The sIL-2R purified from sera of patients with MG had a molecular mass of 45 kDa as the normal sIL-2R. The decline after thymectomy of sIL-2R titers suggests a possible role of the thymus in the occurrence of sIL-2R in the periphery. Soluble IL-2R levels may represent a marker of disease severity in MG, which might be useful in the follow-up of individual patients.

Antibodies to thymic epithelial cells in myasthenia gravis.

The presence of anti-thymus antibodies was investigated in the serum of 36 patients with myasthenia gravis (MG). Using an immunofluorescence technique on frozen thymic sections, we found 45% of patients sera reacting with normal or MG thymuses. Staining was confined to subcapsular and medullary keratin-positive epithelial cells. Thirty-five out of 36 sera from healthy controls and all 15 sera from patients presenting another autoimmune disorder were negative. Antibodies to thymic epithelial cells were almost exclusively detected in patients presenting thymic hyperplasia and did not disappear after thymectomy. They were not clearly associated with antiacetylcholine receptor antibody titer, nor with disease severity. Their strong association to thymic abnormalities highlights the role of the thymus in pathogenesis of MG. The reasons for the appearance of these antibodies, the structure they recognize on thymic epithelial cells and their possible etiological role are discussed.

Cellular aspects of myasthenia gravis.

Several cellular aspects were investigated in a large series of patients with MG. First, non-Ag-specific proliferation was tested by measuring the response to r-IL2. Thymocytes from most MG patients showed hyperactivity to r-IL2. Peripheral blood lymphocytes (PBL) from some patients also showed a high response to r-IL2. These responding patients were generally those tested before thymectomy, presenting a high anti-AChR Ab titer and a severe form of the disease. Second, Ag-specific proliferation of MG PBL was assayed using 8 synthetic peptides corresponding to selected domains of torpedo or human AChR. Only 2 peptides gave a positive response in a significant number of patients, essentially in those presenting high anti-AChR Ab titer. The first is located near the alpha-bungarotoxin binding site and the second is in a cytoplasmic domain, according to models predicting the AChR transmembrane orientation. The positive results were essentially obtained with the human peptides; the corresponding torpedo peptides were positive in very few patients. Both human and torpedo peptides which include a part of the alpha-bungarotoxin binding site were negative. Finally, although morphological abnormalities were clearly visible in thymic hyperplasia, no correlation could be established between the thymus type and the cellular proliferation either to r-IL2, or to the peptides. Overall, our data indicate that cell-dependent mechanisms participate in the pathogenesis of MG, but the level of their involvement deserves further investigation.

In vitro anti-acetylcholine receptor antibody synthesis by myasthenia gravis patient lymphocytes: correlations with thymic histology and thymic epithelial-cell interactions.

In vitro anti-acetylcholine receptor antibody (anti-AChR Ab) production by peripheral blood lymphocytes (PBL) and thymic lymphocytes was investigated in 52 patients with myasthenia gravis (MG). There was a positive correlation between in vitro anti-AChR Ab synthesis and in vivo titers. A relationship between the rates of synthesis by PBL and histological abnormalities of the thymus was also observed. Patients with hyperplastic thymus tended to produce the largest amounts in vitro, while those with an involuted thymus produced little or none. Production in thymoma patients is likely to correlate with the histological nature of the thymus associated with the tumor. In vitro Ab synthesis was modulated by the depletion of a cell subset for half of the patients tested. Finally, anti-AChR Ab production by thymocytes but not by PBL is enhanced by the addition of autologous or allogeneic thymic epithelial cells, suggesting a possible role of thymic epithelial cells in the autosensitization against AChR occurring in the thymus.

The in vivo effects of corticosteroids on thymocyte subsets in myasthenia gravis.

The in vivo effects of corticotherapy on thymocyte subpopulations have been evaluated in patients with myasthenia gravis (MG). Ten patients receiving high-dose, long-term treatment were studied and compared with two control groups (MG untreated patients and normal age-matched subjects). In the treated group, the thymus was generally involuted; the percentage of OKT6+ or OKT4+T8+ thymocytes was profoundly decreased compared to controls. A significant percentage of OKT10 - cells was detected particularly among older patients, suggesting steroid-induced immigration. Conversely the percentage of more mature OKT3+ cells was increased. The balance between OKT4+T8- and OKT4-T8+ cells was unchanged in young patients (less than 40 years old) and increased in the older group. These data show that, as in the mouse, corticosteroids profoundly alter human thymocyte subsets.