Immunosuppressive therapy with rituximab in common variable immunodeficiency

Abstract

Common variable immunodeficiency (CVID) is the most frequent symptomatic primary antibody deficiency in adulthood and is characterized by the marked reduction of IgG and IgA serum levels. Thanks to the successful use of polyvalent immunoglobulin replacement therapy to treat and prevent recurrent infections, non-infectious complications, including autoimmunity, polyclonal lymphoproliferation and malignancies, have progressively become the major cause of morbidity and mortality in CVID patients. The management of these complications is particularly challenging, often requiring multiple lines of immunosuppressive treatments. Over the last 5–10 years, the anti-CD20 monoclonal antibody (i.e., rituximab) has been increasingly used for the treatment of both autoimmune and non-malignant lymphoproliferative manifestations associated with CVID. This review illustrates the evidence on the use of rituximab in CVID. For this purpose, first we discuss the mechanisms proposed for the rituximab mediated B-cell depletion; then, we analyze the literature data regarding the CVID-related complications for which rituximab has been used, focusing on autoimmune cytopenias, granulomatous lymphocytic interstitial lung disease (GLILD) and non-malignant lymphoproliferative syndromes. The cumulative data suggest that in the vast majority of the studies, rituximab has proven to be an effective and relatively safe therapeutic option. However, there are currently no data on the long-term efficacy and side effects of rituximab and other second-line therapeutic options. Further randomized controlled trials are needed to optimize the management strategies of non-infectious complications of CVID.

Rituximab and antimetabolite treatment of granulomatous and lymphocytic interstitial lung disease in common variable immunodeficiency

“…4,31,[39][40][41] In case reports or studies of small numbers of patients with GLILD, corticosteroids, TNF-a inhibitors, MMF, sirolimus, cyclosporin, rituximab monotherapy, abatacept, and immunoglobulin replacement therapy have all been reported to improve GLILD. 3,[42][43][44][45][46][47][48][49][50] In our cohort, we found that a minimum of 6 months of immunoglobulin replacement therapy did not result in improvement of GLILD. Corticosteroid therapy, which is the most commonly used and recommended first-line therapy, 51 was used in 20 of our patients (51%) before referral to our center and was ineffective in treating GLILD.…”

Histology of Interstitial Lung Disease in Common Variable Immune Deficiency

“…Corticosteroids are often used firstline, however, response may be short-lived or incomplete, there are significant side effects associated with protracted use and a proportion of patients are refractory (16,34,36,39). Success with Rituximab, both in combination with azathioprine or mycophenolate mofetil, and as monotherapy, has been reported although controlled trials and long-term outcome data are lacking (40)(41)(42)(43). Elevated levels of B-cell activating factor (BAFF), a cytokine that promotes the maturation and survival of B-cells, within the serum and lungs of patients with CVID-related ILD levels drives B-cell hyperplasia and may account for disease progression in a small proportion of patients (15) with invasive B cells in inappropriate germinal centers (28,44).…”

Current Understanding and Recent Developments in Common Variable Immunodeficiency Associated Autoimmunity

“…For genetically undefined CVID, the use of rituximab for autoimmune cytopenias in CVID is one of the most efficacious and safe treatments. Its use was first documented in 2004 (108), and its efficacy and safety have been wellestablished, especially for ITP (109). While ritixumab's efficacy with autoimmune cytopenias may be in part due to its B-cell depleting properties resulting in depletion of autoantibodies, it is thought that its success in CVID patients is also partially due to its effect on T cells (110), again highlighting the importance of T cell abnormalities in CVID.…”