Uncovering the underhanded: B-cell depletion therapies and severe viral infections – Commentary on ‘Fatal underhanded chronic enterovirus infection associated with anti-CD20 monotherapy for central nervous system demyelinating disease’

In this issue of Multiple Sclerosis Journal, Luciani et al. ¹ report a fatal enteroviral infection in a patient with myelin-oligodendrocyte-glycoprotein (MOG) antibody-associated disease treated with rituximab. She received rituximab 3 months after coxsackievirus B4 meningitis (at the time, CVB4-RNA was still detectable in the blood and B-cell counts were 1/µL). Six months later, she developed central nervous system (CNS) involvement and enteroviral myocarditis, with fatal outcome despite heart transplantation. This sad case emphasises the surreptitious infectious potential of enteroviruses in people treated with B-cell depletion. The best-established infectious risks of rituximab in immunocompromised hosts are hepatitis-B reactivation and enteroviral meningitis, ² but rituximab-associated enterovirus encephalitides in adults have been reported.^3,4 In this case, persistent viraemia 3 months after initial enterovirus infection with CNS complication was a likely indication of incomplete viral clearance and might have suggested caution regarding further rituximab dosing. The case also highlights the uncertainties over long-term use of anti-CD20 therapies and the need to monitor B-cell populations (total CD19⁺ or memory CD19⁺/CD27⁺ B cells) or immunoglobulins, to guide interval dosing. Knowing that incidents can and do happen, which biomarkers should we trust? CD19⁺ B-cell monitoring, with 1% as cutoff for retreatment for the majority of patients, is suggested as a way of mitigating toxicity risk without compromising efficacy.^5,6 The refinement of biomarker monitoring for B-cell depletion would include establishing the value of B-cell percentages versus absolute counts, the individual rate of B-cell recovery and changes in immunoglobulin levels, finding how frequently CD19⁺/CD27⁺ cells need to be checked once the 6-month interval is reached, and whether such dosing interval at patient level will remain optimal over time. In addition, at individual patient level the risk of disabling relapses occurring if B-cell depletion is delayed, should also be considered both in neuromyelitis optica spectrum disorder (NMOSD) and MOG-antibody disease.

Although B-cell-depleting biologicals are generally well tolerated, this case highlights the need for treating clinicians to be mindful of their immunosuppressive potency and to use available, and potentially novel, biomarkers to ensure the best possible vigilance for opportunistic infections.