ObjectiveTo assess the impact of immunosuppressive therapy with cyclophosphamide (CYC) and rituximab (RTX) on serum immunoglobulin (Ig) concentrations and B lymphocyte counts in patients with ANCA-associated vasculitides (AAVs).MethodsRetrospective analysis of Ig concentrations and peripheral B cell counts in 55 AAV patients.ResultsCYC treatment resulted in a decrease in Ig levels (median; interquartile range IQR) from IgG 12.8 g/L (8.15-15.45) to 9.17 g/L (8.04-9.90) (p = 0.002), IgM 1.05 g/L (0.70-1.41) to 0.83 g/L (0.60-1.17) (p = 0.046) and IgA 2.58 g/L (1.71-3.48) to 1.58 g/L (1-31-2.39) (p = 0.056) at a median follow-up time of 4 months. IgG remained significantly below the initial value at 14.5 months and 30 months analyses. Subsequent RTX treatment in patients that had previously received CYC resulted in a further decline in Ig levels from pre RTX IgG 9.84 g/L (8.71-11.60) to 7.11 g/L (5.75-8.77; p = 0.007), from pre RTX IgM 0.84 g/L (0.63-1.18) to 0.35 g/L (0.23-0.48; p<0.001) and from pre RTX IgA 2.03 g/L (1.37-2.50) to IgA 1.62 g/L (IQR 0.84-2.43; p = 0.365) 14 months after RTX. Treatment with RTX induced a complete depletion of B cells in all patients. After a median observation time of 20 months median B lymphocyte counts remained severely suppressed (4 B-cells/µl, 1.25-9.5, p<0.001). Seven patients (21%) that had been treated with CYC followed by RTX were started on Ig replacement because of severe bronchopulmonary infections and serum IgG concentrations below 5 g/L.ConclusionsIn patients with AAVs, treatment with CYC leads to a decline in immunoglobulin concentrations. A subsequent RTX therapy aggravates the decline in serum immunoglobulin concentrations and results in a profoundly delayed B cell repopulation. Surveying patients with AAVs post CYC and RTX treatment for serum immunoglobulin concentrations and persisting hypogammaglobulinemia is warranted.
In CVID patients with suspected celiac disease typing of the HLA loci DQA1 and DQB1 can help to identify those that have a genetic susceptibility for CD. In CVID patients with a celiac-like phenotype but negative for CD-associated HLA-DQ markers, an autoimmune enteropathy (AIE) as part of an extended autoimmune dysregulation needs to be considered. This has important implications for further diagnostics and therapy of these patients.
B-lymphocytes play a pivotal role in ANCA-associated vasculitides (AAV). The homeostasis of peripheral human B-lymphocyte subpopulations is tightly regulated, but may be disturbed in autoimmune disease or following immunosuppressive therapies. To elucidate the effect of immunosuppression and the relevance of B-lymphocyte disturbances, the B-lymphocyte compartment was analysed in 61 AAV patients. After immunosuppressive treatment a general B-lymphocytopenia developed in AAV patients. Within the B-lymphocyte subpopulations transitional B cells are the first maturation stage found in the peripheral blood. Transitional B-lymphocytes were significantly lower in AAV patients after immunosuppressive therapy compared to healthy controls. Furthermore, marginal zone B cells--a B-lymphocyte population protecting against encapsulated bacteria--were markedly lowered after immunosuppressive therapy in AAV patients. AAV patients treated with immunosuppressants had lower numbers of naïve and memory B-lymphocytes. Numbers of marginal zone B cells, memory B cells and plasmablasts correlated with concentrations of immunoglobulins. We evaluated plasmablasts for a potential correlation with disease activity. Different from what has been reported for e.g. large vessel vasculitis, absolute numbers of plasmablasts were not increased in patients with AAV and showed no correlation to disease activity. As low transitional B cells after treatment with immunosuppressants indicated an impaired early B-lymphocyte development, seven patients treated with the B cell depleting agent rituximab (RTX) because of relapsing disease activity were analysed for their B cell repopulation kinetics. In the majority of these patients repopulation of the peripheral B cell compartment by newly formed transitional B cells after RTX treatment was constricted and delayed.
Background B lymphocytes are involved in the pathogenesis of AAVs by the production of cytokines/chemokines and autoantibodies. Immunosuppressive therapy is effective in AAVs but may lead to a decline in serum immunoglobulin (Ig) concentrations and to changes in the peripheral B cell compartment. Objectives To assess the effect of immunosuppressive treatment on the peripheral B cell compartment in AAV patients. Methods In 36 AAV patients a retrospective analysis of Ig concentrations and flowcytometry of peripheral B-cells was conducted. A group of 26 healthy donors served as control. Results 33 of 36 AAV patients were treated with cyclophosphamide (CYC) prior to analysis (median cumulative dose 14.5g; IQR 5.825-30). At the time of analysis 29 patients were treated with prednisone (median dose 5mg/d; IQR 3.75-8.75), eight received methotrexate (MTX), six azathioprine (AZA), six leflunomide (LEF), four mycophenolate mofetile, and eleven patients had no DMARD. Decreased IgG serum concentrations (<7g/L) were detected in 14 patients. Compared to healthy controls absolute cell counts and relative percentages of lymphocytes and CD19+ B cells were significantly decreased in AAV patients (Table 1). Notably, IgD+CD27+ marginal zone B cells were significantly decreased in AAV patients both in absolute cell counts and relative percentages. IgD+CD27- naive B cells, IgD-CD27+ memory B cells, IgA+ B cells, transitional B cells and plasmablasts were significantly decreased in absolute numbers but not in relative percentages. In the subgroup of AZA treated patients absolute numbers of all B cell subpopulations except for IgA+ B cells and plasmablasts were reduced. In LEF treated patients only IgD+CD27+ B cells were reduced. In MTX-treated patients only IgD+CD27+ B cells were reduced both in absolute numbers and percentage while IgD+CD27- and IgD-CD27+ B cells, IgA+ B cells and plasmablasts were decreased only in absolute numbers. Cell typeAAV patientsHealthy controlsp-value Lymphocytes (%)12.3 (7.8-17.5)30.7 (26.4-36)<0.001 Lymphocytes/μl968 (649.25-1366)1893 (1633-2279)<0.001 CD19+ B cells (%)6.2 (2.9-8.9)11.7 (8.4-13)<0.001 CD19+ B cells/μl45 (27-84)190 (132-276)<0.001 IgD+ CD27- B cells (%)58.2 (38.3-84.8)63.0 (51.6-73.6)=0.875 IgD+ CD27- B cells/μl25 (13-63)119 (72-173)<0.001 IgD+ CD27+ B cells (%)9.7 (4.5-18)18.3 (10.9-23.7)=0.004 IgD+ CD27+ B cells/μl4 (2-8)32 (27-48)<0.001 IgD- CD27+ B cells (%)19.2 (8.5-33.5)12.7 (10-18.8)=0.234 IgD- CD27+ B cells/μl6 (4-23)22 (16-39)<0.001 IgA+ B cells (%)9.5 (4.8-17.6)5.8 (4.6-8.6)=0.075 IgA+ B cells/μl4 (2-9)11 (7-18)<0.001 Transitional B cells (%)0.9 (0.3-4.9)1.4 (0.9-2.3)=0.602 Transitional B cells/μl1 (0.7-3)3 (1-5)=0.004 Plasmablasts (%)2.4 (1.1-6.3)1.6 (0.9-2.8)=0.092 Plasmablasts/μl1 (0.4-3)3 (2-5)<0.001 Data in median; interquartile range (IQR). Conclusions Immunosuppressive therapy leads to a decrease in absolute numbers of CD19+ B cells and all examined B cell subpopulations, while IgD+ CD27+ MZ-like B cells showed also a relative decrease. Disclosure of Interest None...
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