Background/Purpose:

Rituximab (RTX) is used in refractory pediatric rheumatic diseases (PRD). Data regarding the effects of RTX on the immune system in children and safety in PRD is scarce. The purpose was to prospectively evaluate indicators of humoral immunity before and until 2 yrs after RTX administration.

Methods: Twenty patients (pts) with PRD (4 SLE, 3 MCTD, 3 JIA, 2 eosinophilic fasciitis, 2 juvenile dermatomyositis, 2 Sjögren-syndrome, 2 GPA (Wegener), 1 MPA, 1 PM/Scl-overlap) after excluding common variable immunodeficiency received at least 1 standard dose RTX cycle (some pts up to 3 cycles). Additional treatment consisted of prednisolone (10), hydroxychloroquin (10), mycophenolate mofetil (9), methotrexate (6), leflunomide (4), abatacept (2), everolimus (2), cyclosporin (1) and antiinflammatory doses of i.v. immunoglobulin (IVIG) (3). Lymphocyte subpopulations, IgA, IgG, IgM and IgE levels, IgG subclasses, isoagglutinins, antigen-specific IgG levels to tetanus toxin, H. influenzae type B (Hib), pneumococcus and measles, spleen size, presence of Howell-Jolly bodies (functional hyposplenism) and throat culture were obtained 6, 12 and 24 months (mos) after RTX. IgG and antigen-specific IgG levels in pts receiving IVIG were not included in the analysis. The continuous variables at time points 6, 12 and 24 mos were compared by paired T test to time point 0 mo (prior to RTX).  

Results:

All pts achieved complete B cell depletion. B cells repopulated in all pts with a median of 8.5 mos. IgG and IgM levels were (mean [standard deviation] mg/dl at 0, 6, 12, 24 months) IgG 1428 [723], 1255 [653], 1075 [452], 1243 [617]; IgM 119 [61], 71 [52], 54 [39], 52 [46]. Significant reductions were observed for IgG (6/12 mos), IgM (6/12/24 mos), IgA (6/12 mos) and IgE (6/12/24 mos). Overall, 7/17 (41%) of patients received IVIG substitution based on predefined IgG and/or IgM threshold levels. One pt developed low IgG2/3, IgA and IgM levels, and 2 pts developed low IgG4 levels, at 24 mos after RTX. Tetanus toxoid IgG decreased significantly at 12 mos but not below a protective threshold in any pt. There was a non-significant decrease in pneumococcal antibodies at 12 and 24 mos. Individually, Hib-IgG and pneumococcal antibodies fell below protective thresholds in some pts. Measles IgG levels decreased significantly at 12 and 24 mos but not below a protective threshold. There was a non-significant decrease in spleen size at 6 months. Transient Howell-Jolly bodies were observed in 8 pts, and antibiotic prophylaxis was begun. Throat culture showed colonization with C. albicans in 12, S. aureus in 3, Hib in 2, both P. aeruginosa and S. marcescens in 1, E. coli in 1 and Enterobacter in 1 pt. One pt developed fever, neutropenia, received i.v. antibiotics and recovered fully.

Conclusion:

Acquired humoral immunodeficiency occasionally occurs after RTX treatment in PRD, especially after repeated treatment cycles. Preventive strategies, including IVIG substitution and/or antibiotic prophylaxis informed by immunologic studies maybe useful in preventing serious invasive infections. We suggest at least 2 yrs of surveillance for acquired humoral immunodeficiency, incl. IgA, IgG, IgM, IgG subclasses and immunization titers after RTX treatment in PRD.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/immunological-risk-factors-after-rituximab-therapy-in-patients-with-pediatric-rheumatic-diseases-a-prospective-single-center-study/