LAUSR

Alemtuzumab is a humanized monoclonal antibody that targets CD52, an antigen expressed on lymphocytes, monocytes, some dendritic cell populations, natural killer cells and other leukocytes. Its exact mechanism of action in patients with multiple sclerosis (MS) is not known. However, it is believed that its therapeutic effects on this condition are not only due to lymphocyte depletion but also to modifications on lymphocyte repopulation and on serum cytokine profile.1 Autoimmune reactions are the most important adverse effects (AEs) reported with its treatment. AEs on thyroid function are the most frequent. Up to 30% of patients in the main clinical trials were affected, although most of them only experienced a mild–moderate reaction. Thrombocytopenia in 2% of treated patients and nephropathy in 0.3%, both related to autoimmune mechanisms, are the two other most frequent AEs notified with its use in MS patients. In addition, a few cases of other cytopenias such as pancytopenia, neutropenia or haemolytic anaemia have been also mentioned in the main trials.1,2 In this issue of the journal, two further cases of autoimmune haemolytic anaemia (AIHA) with very similar clinical features are reported on. Both were life-threatening episodes caused by warm antibodies that started 11 months after alemtuzumab 60 mg (total dose) administration and were solved, in one case, by corticoids and immunoglobulins administration and, in the other, using also red cell units and rituximab. However, in other cases, AIHA has also been reported after longer periods after alemtuzumab therapy initiation and with a higher total dose.3,4 Moreover, in one of the cases reported in this issue of the journal, a slight and temporary glomerular injury that accompanies AIHA crisis is also reported. Although with a very low frequency, some cases of glomerulonephritis have been reported on with alemtuzumab treatment. Some of them were diagnosed with anti-glomerular basement membrane (anti-GBM) disease and some other with membranous glomerulonephritis; and in at least two cases, anti-GBM disease was not solved despite an intensive immunosuppressive therapy and, finally, a renal transplant was required.1 How a medicine used to treat an autoimmune disease such as MS can also be cause of autoimmunity is not very well understood, but several mechanisms have been proposed. One of them point out the way how T-lymphocyte repopulation takes place after their depletion by alemtuzumab treatment. According to this theory, in patients with autoimmune AEs, T-cell repopulation from lymphocytes that escaped depletion by alemtuzumab would prevail over that from generation of new T cells in the thymus. This would result in a lower T-cell pool diversity and a higher autoimmunity caused by the expansion of autoreactive T cells.1,2 In addition, a baseline high circulating levels of IL-21 has been suggested as another factor that would promote autoimmune AEs in these patients. IL-21 would also stimulate autoimmunity by promoting T-cell cycles and increasing the possibility for T cells to find autoantigens and break tolerance.2 In fact, detection of high baseline IL-21 levels has been proposed as a possible biomarker to predict autoimmunity in these patients.5 However, no method has been established up to now to identify patients with a higher risk of developing autoimmune AEs to alemtuzumab therapy. Meanwhile, to communicate all new cases with a serious suspected adverse drug reaction occurring in real world – especially those notified in a low frequency or not at all in clinical trials – is important in order to alert physicians and better define alemtuzumab AEs profile. In addition, in order to avoid them as much as possible, it also seems appropriate to reserve alemtuzumab treatment for patients with an aggressive MS course and strictly follow all advice recommended for patients treated with this medicine.