Long-term treatment with rituximab (RTX) is associated with a high risk for hypogammaglobulinemia (hypo-Ig) and reduction in antitetanus protection in patients with the inflammatory auto-immune diseases known as neuromyelitis optica spectrum disorders (NMOSDs), with the monitoring of total and specific immunoglobulin (Ig) levels before and during RTX therapy possibly preventing hypo–Ig-related complications. An observational, retrospective case series study was conducted at the Regional Reference Centre for Multiple Sclerosis at Orbassano in Turin, Italy, with results published in Neurology Neuroimmunology & Inflammation.

The investigators sought to assess the long-term effects of RTX on total and specific Igs among patients with NMOSDs. They evaluated total IgG, IgA, and IgM levels in 15 patients with NMOSDs who received treatment with RTX. The median follow-up was 70 months. Antiaquaporin 4 (AQP4)-IgG titration was performed in the samples from 9 patients who tested positive for AQP4 antibodies. In addition, antitetanus, antivaricella zoster virus, and anti-Epstein-Barr virus nuclear antigen IgGs were tested in patients with NMOSDs and in 6 healthy control participants.

Rituximab therapy was associated with annual reductions in total IgG of 0.42 g/L/year (95% CI, −0.49 to −0.35; P <.0001), in total IgA of 0.08 g/L/year (95% CI, −0.09 to −0.06; P <.0001), and in total IgM of 0.07 g/L/year (95% CI, −0.09 to −0.06; P <.0001). Hypo-Ig (ie, IgG <7 g/L) was reported in 11 of 15 patients. Moreover, severe hypo-Ig (ie, IgG <4 g/L) was reported in 3 (20%) of 15 patients, 2 of whom reported serious infectious complications.

Group analysis demonstrated that anti-AQP4 IgG titers were decreased with the use of RTX over time, with a link observed between anti-AQP4 IgG titers and total IgG levels observed. Furthermore, the effects of RTX were reported with respect to pathogen-specific IgGs. Of note, antitetanus IgG levels in patients with NMOSDs were significantly lower than those in healthy control participants. The half-life of antitetanus IgG was reduced by approximately 50% in patients with NMOSDs when compared with the general population.

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The investigators concluded that the long-term use of RTX is associated with the risk for hypo-Ig and reduction in antitetanus protection among patients with NMOSDs. Additional studies that involve a larger number of participants are warranted to evaluate similar effects of other anti-CD20 agents used for the treatment of central nervous system autoimmune disorders and thus optimize the clinical management of individuals with these disorders.


Marcinnò A, Marnetto F, Valentino P, et al. Rituximab-induced hypogammaglobulinemia in patients with neuromyelitis optica spectrum disorders. Neurol Neuroimmunol Neuroinflamm. 2018;5(6):e498.