Advances in therapies directed to lymphocytes in systemic lupus erythematosus
Source: immedicohospitalario.es
Systemic lupus erythematosus (SLE) is an autoimmune disease with multifaceted and extremely variable clinical manifestations, characterized by relapses and outbreaks followed by periods of remission. Until recently, the management of the disease has been based on non-steroidal anti-inflammatories, glucocorticoids, immunosuppressants and hydroxychloroquine. Although these agents have improved the prognosis of SLE, they still present adverse effects and are ineffective in refractory disease. Hence the need to develop new therapies. The treatments currently in advanced clinical phase are mainly aimed at restoring the immunological tolerance.
Therapies directed to B lymphocytes
Belimumab has been the first targeted biological therapy in the LES. This antibody is targeted to the soluble lymphocyte stimulating protein, known as BLyS. Its efficacy and safety have been evaluated in the international phase III studies BLISS 52 and BLISS 76, with more than 1600 patients with mild or moderate disease and without renal or central nervous system involvement. Belimumab improved the global activity of the disease in the most common musculoskeletal and mucocutaneous domains. The improvement was greater in patients with high serum levels of anti-double-stranded DNA and low complement antibodies. The treatment was associated with a reduction of the median CD20 + B lymphocytes, preserving memory B and T lymphocyte populations. The results of both studies also suggest that the combination of belimumab with mycophenolate mofetil, standard therapy in SLE, can offer benefit in the renal outcome of the disease. This finding is expected to be confirmed in an additional phase III study in patients with active nephritic lupus.
Atacicept is another inhibitor of B lymphocyte activation, blocking the BLyS and APRIL molecules. The concept of this new therapy is based on the observation that patients affected by SLE and other autoimmune diseases have high levels of both molecules. Although initially it had been theorized that dual inhibition may have as an additional advantage the ability to inhibit long-lived plasma cells, the results of the clinical trials carried out with this drug have revealed both the risk of toxicity, in terms of infections and hypogammaglobulinemia, as well as efficacy, since the treatment failed to reduce the rate of outbreaks.
The overexpression of BAFF in the LES, a molecule of activation and differentiation of the B lymphocytes, as well as the correlation of their serum levels with the activity of the disease, has led to the development of bilsimimod, a subcutaneous biological agent inhibitor of BAFF. The first clinical study showed that bilsimimod has a tolerability comparable to placebo and induces significant changes in subpopulations of B lymphocytes, with an increase in memory cells and a reduction in virgins. In the subsequent phase II study, patients with severe disease treated with glucocorticoids particularly benefited from the higher dose of bilsimimod. Its safety and efficacy as an addition to standard therapy are currently being evaluated in a phase III study.
Tabalumab is another biological agent targeted to the same target, neutralizing BAFF in both the cell membrane and soluble form. The phase III ILLUMINATE-1 and -2 studies with this agent have yielded variable results. Although the first one did not reach its primary and secondary objective, the response rate in the treatment group was higher than in the placebo group. In ILLUMINATE-2, 38% of patients reached the primary objective at 52 weeks with one dose every two weeks, a value higher than that observed with placebo. In this trial, tabalumab showed greater efficacy in serologically active patients. In none of the two trials was significant impact of tabalumab on relevant renal parameters in the LSE, such as glomerular filtration rate, serum creatinine or renal outbreaks, among others.
At Distefar we support these advances that are linking to the development of new immunological therapies.
