Immunoglobulin G treatment of secondary immunodeficiencies in the era of novel therapies.

Abstract

The demonstration of poor vaccine responses, together with low immunoglobulin (Ig) levels, are the mainstay of clinical diagnosis of antibody deficiency requiring IgG replacement therapy (IgGRT) 1. Hypogammaglobulinaemia refers to the finding of low Ig levels in the blood and acts only as a surrogate marker for antibody deficiency. In general, secondary antibody deficiencies caused by different immunomodulatory treatments are poorly studied. This is especially true with regard to systematic assessment of serological vaccine responses to T dependent protein and T independent polysaccharide antigens in patients with secondary hypogammaglobulinaemia. Although the backbone of most immunomodulatory regimens includes glucocorticoids, the effects of glucocorticoids on polysaccharide responses are insufficiently known. This causes further difficulties in differentiating primary and secondary antibody deficiencies from each other 2. The best-studied secondary antibody deficiencies are those found together with lymphoproliferative malignancies. Compared to historical controls, IgGRT has been shown to increase primary antibody deficient patients' life expectancy by more than 30 years 3. With the increasing use of cytotoxic and biological therapies against lymphoproliferative and autoimmune diseases and in organ transplantation, secondary immunodeficiencies with symptomatic hypogammaglobulinaemia are seen more commonly 4,5. The available studies on IgGRT in chronic lymphocytic leukaemia (CLL) and multiple myeloma (MM) have recruited small numbers of patients and were performed mainly more than 20 years ago. Modes of chemotherapy used then differ greatly from contemporary treatment. Furthermore, the overall prognosis was much poorer, follow-up times in the studies were short and, unsurprisingly, no effect on overall survival was shown. There are even fewer available data on substitution therapy in lymphoma survivors with hypogammaglobulinaemia, although newer anti-CD20 therapies may have increased their incidence. Surprisingly, although long-term glucocorticoids have been used for decades, we also have insufficient knowledge on the exact magnitude and duration of suppression of vaccine responses and of Ig production caused by glucocorticoids. The available data on symptomatic hypogammaglobulinaemia and IgGRT in patients with CLL and MM following lymphoma treatment and in autoimmune diseases are reviewed.