Rituximab Effects More Than B Cells in Rheumatoid Arthritis

SORRENTO, ITALY — Evolving experience with rituximab is demonstrating that this monoclonal antibody has multiple complex effects other than B-cell depletion in rheumatoid arthritis, including the alteration of macrophage function, Dr. Elias Toubi said at the Fifth International Congress on Autoimmunity.

B cells have multiple immunomodulatory functions that may be involved in autoimmunity. Aside from the production of antibodies such as rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP), other B-cell functions in RA and other autoimmune diseases include the production of proinflammatory cytokines, regulation of other effector cells, and acting as antigen-presenting cells. Dr. Toubi of Bnai Zion Medical Center, Haifa, Israel and his colleagues studied 10 patients with RA who had previously been treated with methotrexate without benefit.

Baseline assessments included measurement of serum RF, anti-CCP, and total IgG. Also, blood monocyte-derived macrophages were analyzed for messenger RNA expression of the costimulatory molecule CD86, the immunoregulatory cytokine interleukin (IL)-10, and B cell-activating factor (BAFF), he said.

The 10 patients then underwent a single course of rituximab therapy, which consisted of two infusions of 1,000 mg 2 weeks apart. B cells were depleted at 2 and 4 months in all patients. The mean B-cell count at baseline was 199 cells/mm

Six patients achieved an ACR 50 response and were classified as responders. An additional two had partial responses, and two failed to respond.

At baseline, seven of the patients had been positive for RF and anti-CCP. Among responders RF titers fell or disappeared, but the anti-CCP antibody levels remained high.

Because anti-CCP antibodies are produced by B cells, their persistence in the context of overall B-cell depletion suggests that certain pathogenic memory B cells survive, possibly in secondary lymphoid tissue, according to Dr. Toubi.

Treatment with rituximab also altered the expression of BAFF and IL-10, as was shown in an analysis of the supernatant of cultured macrophages.

The increased expression of these factors reflects compensatory efforts to restore B-cell homeostasis, he explained.

In cultured macrophages, the expression of messenger RNA of CD86 also was increased following treatment, reflecting the maintenance of a protective immune response despite depletion (Ann. Rheum. Dis. 2006; doi:10.1136/ard.2006.062505

Furthermore, and most important, a significant reduction in tumor necrosis factor (TNF)-α following treatment also was seen in macrophages, Dr. Toubi said.

Immature macrophages are dominant in RA and are the primary producers of proinflammatory TNF-α, and a decrease in this cytokine following treatment with rituximab suggests that the immature macrophages are being replaced following depletion by more mature, less inflammatory macrophages, he said.

SORRENTO, ITALY — Evolving experience with rituximab is demonstrating that this monoclonal antibody has multiple complex effects other than B-cell depletion in rheumatoid arthritis, including the alteration of macrophage function, Dr. Elias Toubi said at the Fifth International Congress on Autoimmunity.

B cells have multiple immunomodulatory functions that may be involved in autoimmunity. Aside from the production of antibodies such as rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP), other B-cell functions in RA and other autoimmune diseases include the production of proinflammatory cytokines, regulation of other effector cells, and acting as antigen-presenting cells. Dr. Toubi of Bnai Zion Medical Center, Haifa, Israel and his colleagues studied 10 patients with RA who had previously been treated with methotrexate without benefit.

Baseline assessments included measurement of serum RF, anti-CCP, and total IgG. Also, blood monocyte-derived macrophages were analyzed for messenger RNA expression of the costimulatory molecule CD86, the immunoregulatory cytokine interleukin (IL)-10, and B cell-activating factor (BAFF), he said.

The 10 patients then underwent a single course of rituximab therapy, which consisted of two infusions of 1,000 mg 2 weeks apart. B cells were depleted at 2 and 4 months in all patients. The mean B-cell count at baseline was 199 cells/mm

Six patients achieved an ACR 50 response and were classified as responders. An additional two had partial responses, and two failed to respond.

At baseline, seven of the patients had been positive for RF and anti-CCP. Among responders RF titers fell or disappeared, but the anti-CCP antibody levels remained high.

Because anti-CCP antibodies are produced by B cells, their persistence in the context of overall B-cell depletion suggests that certain pathogenic memory B cells survive, possibly in secondary lymphoid tissue, according to Dr. Toubi.

Treatment with rituximab also altered the expression of BAFF and IL-10, as was shown in an analysis of the supernatant of cultured macrophages.

The increased expression of these factors reflects compensatory efforts to restore B-cell homeostasis, he explained.

In cultured macrophages, the expression of messenger RNA of CD86 also was increased following treatment, reflecting the maintenance of a protective immune response despite depletion (Ann. Rheum. Dis. 2006; doi:10.1136/ard.2006.062505

Furthermore, and most important, a significant reduction in tumor necrosis factor (TNF)-α following treatment also was seen in macrophages, Dr. Toubi said.

Immature macrophages are dominant in RA and are the primary producers of proinflammatory TNF-α, and a decrease in this cytokine following treatment with rituximab suggests that the immature macrophages are being replaced following depletion by more mature, less inflammatory macrophages, he said.

SORRENTO, ITALY — Evolving experience with rituximab is demonstrating that this monoclonal antibody has multiple complex effects other than B-cell depletion in rheumatoid arthritis, including the alteration of macrophage function, Dr. Elias Toubi said at the Fifth International Congress on Autoimmunity.

B cells have multiple immunomodulatory functions that may be involved in autoimmunity. Aside from the production of antibodies such as rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP), other B-cell functions in RA and other autoimmune diseases include the production of proinflammatory cytokines, regulation of other effector cells, and acting as antigen-presenting cells. Dr. Toubi of Bnai Zion Medical Center, Haifa, Israel and his colleagues studied 10 patients with RA who had previously been treated with methotrexate without benefit.

Baseline assessments included measurement of serum RF, anti-CCP, and total IgG. Also, blood monocyte-derived macrophages were analyzed for messenger RNA expression of the costimulatory molecule CD86, the immunoregulatory cytokine interleukin (IL)-10, and B cell-activating factor (BAFF), he said.

The 10 patients then underwent a single course of rituximab therapy, which consisted of two infusions of 1,000 mg 2 weeks apart. B cells were depleted at 2 and 4 months in all patients. The mean B-cell count at baseline was 199 cells/mm

Six patients achieved an ACR 50 response and were classified as responders. An additional two had partial responses, and two failed to respond.

At baseline, seven of the patients had been positive for RF and anti-CCP. Among responders RF titers fell or disappeared, but the anti-CCP antibody levels remained high.

Because anti-CCP antibodies are produced by B cells, their persistence in the context of overall B-cell depletion suggests that certain pathogenic memory B cells survive, possibly in secondary lymphoid tissue, according to Dr. Toubi.

Treatment with rituximab also altered the expression of BAFF and IL-10, as was shown in an analysis of the supernatant of cultured macrophages.

The increased expression of these factors reflects compensatory efforts to restore B-cell homeostasis, he explained.

In cultured macrophages, the expression of messenger RNA of CD86 also was increased following treatment, reflecting the maintenance of a protective immune response despite depletion (Ann. Rheum. Dis. 2006; doi:10.1136/ard.2006.062505

Furthermore, and most important, a significant reduction in tumor necrosis factor (TNF)-α following treatment also was seen in macrophages, Dr. Toubi said.

Immature macrophages are dominant in RA and are the primary producers of proinflammatory TNF-α, and a decrease in this cytokine following treatment with rituximab suggests that the immature macrophages are being replaced following depletion by more mature, less inflammatory macrophages, he said.