Association between hypogammaglobulinaemia and severe infections during induction therapy in ANCA-associated vasculitis: from J-CANVAS study

Abstract

Objectives To investigate the association between decreased serum IgG levels caused by remission-induction immunosuppressive therapy of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and the development of severe infections. Methods We conducted a retrospective cohort study of patients with new-onset or severe relapsing AAV enrolled in the J-CANVAS registry, which was established at 24 referral sites in Japan. The minimum serum IgG levels up to 24 weeks and the incidence of severe infection up to 48 weeks after treatment initiation were evaluated. After multiple imputations for all explanatory variables, we performed the multivariate analysis using a Fine-Gray model to assess the association between low IgG (the minimum IgG levels < 500 mg/dl) and severe infections. In addition, the association was expressed as a restricted cubic spline (RCS) and analysed by treatment subgroups. Results Of 657 included patients (microscopic polyangiitis, 392; granulomatosis with polyangiitis, 139; eosinophilic granulomatosis with polyangiitis, 126), 111 (16.9%) developed severe infections. The minimum serum IgG levels were measured in 510 patients, of whom 77 (15.1%) had low IgG. After multiple imputations, the confounder-adjusted hazard ratio of low IgG for the incidence of severe infections was 1.75 (95% confidence interval: 1.03–3.00). The RCS revealed a U-shaped association between serum IgG levels and the incidence of severe infection with serum IgG 946 mg/dl as the lowest point. Subgroup analysis showed no obvious heterogeneity between treatment regimens. Conclusion Regardless of treatment regimens, low IgG after remission-induction treatment was associated with the development of severe infections up to 48 weeks after treatment initiation.

Rituximab induction and reinduction in granulomatosis with polyangiitis and microscopic polyangiitis: A retrospective multicenter study in Taiwan

“…In addition to bacterial infection, there were also invasive aspergillosis and CMV retinitis, pneumonitis, and viremia, which were impressive considering our small sample size. Previous studies revealed the risk of infection is higher in the aged, patients with higher baseline creatinine, higher prednisolone dose, or hypogammaglobulinemia 29,39,45 . In our patients, the median of maximum daily prednisolone dose is about half of the initial dose in the PLEXIVAS trial for severe ANCA‐associated vasculitis (Table S2), 29 but the incidence of infection was still significant.…”

“…Previous studies revealed the risk of infection is higher in the aged, patients with higher baseline creatinine, higher prednisolone dose, or hypogammaglobulinemia. 29,39,45 In our patients, the median of maximum daily prednisolone dose is about half of the initial dose in the PLEXIVAS trial for severe ANCA-associated vasculitis (Table S2), 29 but the incidence of infection was still significant. Clinically we estimated the infection risk by initial IgG levels (Table S2), however, a recent study suggested that the minimum of post-treatment IgG levels is important for the risk estimation.…”

“…A previous study demonstrated that regular treatment every 6 months or 24 weeks is associated with a better disease control 7 . However, hypogammaglobulinemia is a rare but critical safety concern under regular rituximab therapy, 37,38 which may increase infection risk 39 . On the other hand, reinduction after a relapse may be effective and cost‐saving, 9,40 especially in areas with limited health care resources.…”

“…In our patients, the median of maximum daily prednisolone dose is about half of the initial dose in the PLEXIVAS trial for severe ANCA‐associated vasculitis (Table S2), 29 but the incidence of infection was still significant. Clinically we estimated the infection risk by initial IgG levels (Table S2), however, a recent study suggested that the minimum of post‐treatment IgG levels is important for the risk estimation 39 . The risk of CMV infection has also been reported in patients with AAV, 46,47 and CMV infection is associated with other infections and thromboembolism 48,49 .…”

“…Clinically we estimated the infection risk by initial IgG levels (Table S2), however, a recent study suggested that the minimum of post-treatment IgG levels is important for the risk estimation. 39 The risk of CMV infection has also been reported in patients with AAV, 46,47 and CMV infection is associated with other infections and thromboembolism. 48,49 In our patients, infection affected the composite outcome of ESRD or death in patients as previous literature.…”