Rituximab is an effective therapy for remission induction in patients with multi-system autoimmune disease [1, 2, 26, 29]. However, the majority of patients will relapse after a single course [3, 5]. Further courses are effective, although concerns surround the long term effect on humoral immunity and infection risk with repeated rituximab use [30, 31]. Rituximab depletes CD20+ B cells for an average of 6–12 months. Mature plasma cells (the source of 95% of circulating IgG) do not express CD20; however, prolonged depletion of plasma cell precursors may reduce replenishment of mature plasma cells leading to hypogammaglobulinaemia and infection risk.
We studied the frequency and severity of hypogammaglobulinaemia and severe infections following repeated rituximab dosing in patients with multi-system autoimmune disease. Low IgG, IgM and IgA levels were more frequent before first rituximab (13%, 10% and 10% of patients respectively) than in NHL or RA [16, 17, 32–34]. At 60 months, the proportion of patients with low IgG remained stable (14%) however, those with low IgM or IgA rose to 25% (p = 0.018) and 17% (p = 0.211) respectively. The increase in proportion of patients with IgM <0.4 g/L following rituximab, is consistent with previous data in SLE and AAV patients [3, 20–23, 26]. Low levels of IgG, IgM and IgA occurred in 34%, 51% and 23% of patients for at least 3 consecutive months at any time during follow-up. In keeping with the overall stabile proportion of patients with low IgG during follow-up, the majority of episodes of IgG hypogammaglobulinaemia were mild or transient, and only a minority suffered moderate/severe prolonged IgG hypogammaglobulinaemia. IgG levels were lower at baseline in patients who had received prior cyclophosphamide treatment. However, the development of IgG hypogammaglobulinaemia was not associated with prior cyclophosphamide exposure, but was associated with a higher cumulative corticosteroid exposure during follow-up. Median IgG levels trended downwards in those who received >6 g rituximab, although this did not reach statistical significance.
Our study is retrospective and whilst it does represent real life event rates of hypogammaglobulinaemia and severe infections, in patients with complex multisystem autoimmune disease treated with rituximab, outcomes are confounded by clinical strategies to reduce infection risk, and concomitant therapies that contribute to hypogammaglobulinaemia and infection risk. In our practice repeat rituximab dosing is used to treat and prevent disease flare irrespective of peripheral blood B cell count. Immunoglobulins are monitored at each clinic visit. Concomitant immunosuppressive therapies are generally not used alongside rituximab and during follow-up corticosteroids are reduced or withdrawn. In patients with repeated infections, antibiotic prophylaxis is employed; and in patients with infections despite antibiotics and moderate/severe hypogammaglobulinaemia (IgG < 5 g/l), IVIG replacement is used. Discontinuation of further rituximab dosing is considered in patients with IgG < 5 g/l with a downward (rather than stable) trajectory and recurrent infections; however, this decision is balanced against ongoing disease activity, the efficacy benefit derived from rituximab and the availability of other therapeutic options.
Existing data supports the safety of repeated doses of rituximab in RA and NHL, where stable infection rates were observed following initiation of rituximab treatment [33, 35, 36]. We observed infections in 38% of patients in the first year of treatment; similar to rates seen in other studies in primary systemic vasculitis [1, 2, 37, 38] where active disease, chronic lung and kidney disease, prior cyclophosphamide and high corticosteroid exposure also contribute to infection risk. As in RA and NHL, the occurrence of persistent mild hypogammaglobulinaemia (IgG 5–6 g/l) following rituximab was not associated with a higher infection rate [33, 35, 36]. Unlike other populations, where IgG levels <5 g/l have been associated with infection risk , we did not observe an association; however, regular monitoring, antibiotic prophylaxis and IVIG replacement may have reduced infection rates in this subgroup.
Overall we observed a reduction in severe infection rates over time, along with improved disease control, a minimisation of corticosteroids and avoidance of concomitant immunosuppression. Our data suggest that provided careful monitoring is employed together with judicious use of prophylactic therapies, the IgM hypogammaglobulinaemia, transient mild/moderate IgG hypogammaglobulinaemia or occasional severe IgG hypogammaglobulinaemia observed with repeat rituximab dosing are not dominant factors in infection risk in a severe multisystem autoimmune disease population.