Rituximab-Induced Hypogammaglobulinemia and Risk of Infection in Neuromyelitis Optica Spectrum Disorders

Kim, Suhyun; Park, Na Young; Kim, Ki Hoon; Hyun, Jae‐Won; Kim, Ho Jin

doi:10.1212/nxi.0000000000001179

Cited by 23 publications

(30 citation statements)

References 29 publications

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“…While the use and experience of rituximab in NMOSD comprise more than 15 years, controlled safety data are limited. The safety profile of rituximab is generally acceptable but may depend on factors, such as age, gender, weight, disability, duration of therapy, and history of prior immunosuppressive therapies [ 22 , 107 , 228 ]. Most adverse events observed in the RIN-1 study and its open-label extension (OLE) RIN-2 study were mild and infusion-related (Table 1 ) [ 216 , 217 ].…”

Section: Treatment Of Nmosd: General Aspects and Outcome Measuresmentioning

confidence: 99%

“…Most adverse events observed in the RIN-1 study and its open-label extension (OLE) RIN-2 study were mild and infusion-related (Table 1 ) [ 216 , 217 ]. The risk of hypogammaglobulinemia and ensuing infections, which typically comprise infections of the upper respiratory and urinary tract, increases with treatment duration [ 15 , 107 , 141 , 198 , 228 ]. Serology testing for hepatitis B virus (HBV) is mandatory as there is a potentially life-threatening but avoidable risk of reactivation.…”

Section: Treatment Of Nmosd: General Aspects and Outcome Measuresmentioning

confidence: 99%

See 1 more Smart Citation

Update on the diagnosis and treatment of neuromyelitis optica spectrum disorders (NMOSD) – revised recommendations of the Neuromyelitis Optica Study Group (NEMOS). Part II: Attack therapy and long-term management

Kuempfel¹,

Giglhuber²,

Aktaş³

et al. 2023

J Neurol

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This manuscript presents practical recommendations for managing acute attacks and implementing preventive immunotherapies for neuromyelitis optica spectrum disorders (NMOSD), a rare autoimmune disease that causes severe inflammation in the central nervous system (CNS), primarily affecting the optic nerves, spinal cord, and brainstem. The pillars of NMOSD therapy are attack treatment and attack prevention to minimize the accrual of neurological disability. Aquaporin-4 immunoglobulin G antibodies (AQP4-IgG) are a diagnostic marker of the disease and play a significant role in its pathogenicity. Recent advances in understanding NMOSD have led to the development of new therapies and the completion of randomized controlled trials. Four preventive immunotherapies have now been approved for AQP4-IgG-positive NMOSD in many regions of the world: eculizumab, ravulizumab - most recently-, inebilizumab, and satralizumab. These new drugs may potentially substitute rituximab and classical immunosuppressive therapies, which were as yet the mainstay of treatment for both, AQP4-IgG-positive and -negative NMOSD. Here, the Neuromyelitis Optica Study Group (NEMOS) provides an overview of the current state of knowledge on NMOSD treatments and offers statements and practical recommendations on the therapy management and use of all available immunotherapies for this disease. Unmet needs and AQP4-IgG-negative NMOSD are also discussed. The recommendations were developed using a Delphi-based consensus method among the core author group and at expert discussions at NEMOS meetings.

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Section: Treatment Of Nmosd: General Aspects and Outcome Measuresmentioning

confidence: 99%

Section: Treatment Of Nmosd: General Aspects and Outcome Measuresmentioning

confidence: 99%

Update on the diagnosis and treatment of neuromyelitis optica spectrum disorders (NMOSD) – revised recommendations of the Neuromyelitis Optica Study Group (NEMOS). Part II: Attack therapy and long-term management

Kuempfel¹,

Giglhuber²,

Aktaş³

et al. 2023

J Neurol

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“…Nonetheless, it is possible that low IgG may not necessarily impact infection risk given that rituximab only partially depletes B cells in the bone marrow and lymphoid organs and thus may spare enough B-cells in other tissues to maintain adequate humoral immunity. 23,32 Observations from the cohort of patients who took extended treatment holidays during the COVID-19 pandemic suggest that anti-CD20 therapy withdrawal during a median period of 18 months was associated with increasing IgG levels and no change in infection frequency or severity. No patients in our cohort relapsed during the treatment holiday, and only two patients experienced early B-cell repopulation.…”

Section: Discussionmentioning

confidence: 99%

“…Higher EDSS scores are associated with infection risk, 23 but insufficient data was available in our medical records to consistently assess neurological status as measured by the EDSS. Also, the number of yearly infections was potentially underestimated, as some infections were likely not documented in the records.…”

Section: Discussionmentioning

confidence: 99%

Hypogammaglobulinemia secondary to B-cell depleting therapies in neuroimmunology: Comparing management strategies

Kelly

Vishnevetsky

Chibnik

et al. 2023

Multiple Sclerosis Journal - Experimental, Translational and Cl

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Background Anti-CD20 agents are commonly used in MS, NMOSD, and MOGAD. Few studies have compared strategies to address hypogammaglobulinemia. Objective To compare strategies to manage secondary hypogammaglobulinemia in neuroimmunology patients, including reducing anti-CD20 dose and dosing frequency, IVIG/SCIG, anti-CD20 cessation, and DMT switches. Methods All MS, NMOSD, and MOGAD patients at our institution with hypogammaglobulinemia on anti-CD20 agents from 2001 to 2022 were analyzed. The median change in IgG, infection frequency, and infection severity before and after the treatment was calculated. Results In total, 257 patients were screened, and 30 had a treatment for hypogammaglobulinemia. IVIG/SCIG yielded the largest increase in IgG per year (674.0 mg/dL), followed by B-cell therapy cessation (34.7 mg/dL), and DMT switch (5.9 mg/dL). Dose reduction had the largest decrease in yearly infection frequency (2.7 fewer infections), followed by IVIG/SCIG (2.5 fewer), DMT switch (2 fewer), and reduced dosing frequency (0.5 fewer). Infection grade decreased by 1.9 for reduced dosing frequency (less severe infections), by 1.3 for IVIG/SCIG, and by 0.6 for DMT switch. Conclusion This data suggests that IVIG/SCIG may yield the greatest recovery in IgG while also reducing infection frequency and severity. Stopping anti-CD20 therapy and/or switching DMTs also increase IgG and may lower infection risk.

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“…Maintained rituximab treatments induce a progressive secondary hypogammaglobulinemia. 11 It may be sustained for years after rituximab discontinuation and may require immunoglobulin replacement therapies in profound symptomatic cases. 12 Secondary lymphopenia and neutropenia have also been described.…”

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confidence: 99%

Rituximab De-escalation in Patients With Neuromyelitis Optica Spectrum Disorder

et al. 2023

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Background and Objectives:Exit strategies such as de-escalations have not been evaluated for rituximab in patients with neuromyelitis optica spectrum disorder (NMOSD). We hypothesized that they are associated with disease reactivations and aimed to estimate this risk.Methods:We describe a case series of real-world de-escalations from the French NMOSD registry (NOMADMUS). All patients met the 2015 IPND diagnostic criteria for NMOSD. A computerized screening of the registry extracted patients with rituximab de-escalations and at least 12 months of subsequent follow-up. We searched for 7 de-escalation regimens: scheduled discontinuations or switches to an oral treatment after single infusion cycles, scheduled discontinuations or switches to an oral treatment after periodic infusions, de-escalations before pregnancies, de-escalations after tolerance issues, and increased infusion intervals. Rituximab discontinuations motivated by inefficacy or for unknown purposes were excluded. The primary outcome was the absolute risk of NMOSD reactivation (one or more relapses) at 12 months. AQP4+ and AQP4- serotypes were analyzed separately.Results:We identified 137 rituximab de-escalations between 2006 and 2019 that corresponded to a predefined group: 13 discontinuations after a single infusion cycle, 6 switches to an oral treatment after a single infusion cycle, 9 discontinuations after periodic infusions, 5 switches to an oral treatment after periodic infusions, 4 de-escalations before pregnancies, 9 de-escalations after tolerance issues, and 91 increased infusion intervals. No group remained relapse-free over the whole de-escalation follow-up (mean: 3.2 years; range: 0.79 - 9.5), except pregnancies in AQP+ patients. In all groups combined, and within 12 months, reactivations occurred after 11/119 de-escalations in patients with AQP4+ NMOSD (9.2%, CI95% [4.7; 15.9]), from 0.69 to 10.0 months, and in 5/18 de-escalations in patients with AQP4- NMOSD (27.8%, CI95% [9.7; 53.5]), from 1.1 to 9.9 months.Discussion:There is a risk of NMOSD reactivation whatever the rituximab de-escalation regimen.Trial Registration Information:Registered on ClinicalTrials.gov:NCT02850705.Classification of Evidence:This study provides Class IV evidence that de-escalation of rituximab increases the probability of disease reactivation.

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Rituximab-Induced Hypogammaglobulinemia and Risk of Infection in Neuromyelitis Optica Spectrum Disorders

Cited by 23 publications

References 29 publications

Update on the diagnosis and treatment of neuromyelitis optica spectrum disorders (NMOSD) – revised recommendations of the Neuromyelitis Optica Study Group (NEMOS). Part II: Attack therapy and long-term management

Update on the diagnosis and treatment of neuromyelitis optica spectrum disorders (NMOSD) – revised recommendations of the Neuromyelitis Optica Study Group (NEMOS). Part II: Attack therapy and long-term management

Hypogammaglobulinemia secondary to B-cell depleting therapies in neuroimmunology: Comparing management strategies

Rituximab De-escalation in Patients With Neuromyelitis Optica Spectrum Disorder

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