Long-term Tocilizumab Therapy Effective in Regulating Lymphocytes and Neutrophils in NMOSD

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A recent analysis revealed a reduction in regulatory lymphocyte subsets in patients with NMOSD before tocilizumab therapy, with subsequent restoration to normal levels after 1 year treatment.

Takashi Yamamura, MD, PhD, specially appointed professor, department of therapeutics for multiple system atrophy, Graduate School of Medicine and Faculty of Medicine, Kyoto University

Takashi Yamamura, MD, PhD

A new analysis of 2 open-label clinical studies (UMIN000005889; UMIN000007866) published in Neurology Neuroimmunology & Neuroinflammation showed that tocilizumab (Actemra; Genetech), an anti-IL-6 receptor (IL-6R) therapy, positively altered numbers of lymphocytes and neutrophils in patients with neuromyelitis optica spectrum disorder (NMOSD). According to the investigators, the number of alterations restored by the anti–IL-6R therapy suggests its signaling role in the regulation of neutrophils and regulatory lymphocytes in this patient population.1

Using flow cytometry and DNA microarray analysis, investigators observed that 7 patients with NMOSD demonstrated a reduction in the numbers of lymphocyte subsets with regulatory functions, including transitional B cells, CD56high NK cells, and CD45RA-FoxP3high regulatory T cells prior to tocilizumab therapy. Authors noted that after initiating the treatment for 1 year, the numbers increased to normal levels among the same set of patients.

Top Clinical Takeaways

  • Tocilizumab's positive alterations in lymphocyte and neutrophil numbers suggest its potential as a therapeutic option for restoring immune balance in NMOSD.
  • The study indicates tocilizumab's impact on regulatory lymphocytes may contribute to a tightened immune network, explaining its delayed therapeutic effects in preventing relapse.
  • Gene expression analysis revealed the reversal of neutrophil-related alterations after tocilizumab therapy, providing valuable insights for constructing personalized strategies in the treatment of NMOSD.

“In patients with active NMOSD not treated with molecular targeting drugs, we observed reduction or deficiency in lymphocytes with regulatory potentials and activation of neutrophils. However, introduction of anti-IL-6R therapy accompanied by tapering concomitant drugs corrected such abnormalities, which might contribute to persistent relapse prevention,” senior author Takashi Yamamura, MD, PhD, specially appointed professor, department of therapeutics for multiple system atrophy, Graduate School of Medicine and Faculty of Medicine, Kyoto University, and colleagues wrote.1 “The recovery in the naïve T-cell division after starting tocilizumab may underlie the relatively low risk of infection in patients under anti-IL-6R therapy.”

READ MORE: Revised Recommendations Published to Improve Diagnosis and Treatment in NMOSD

In this analysis, investigators assessed the long-term effects of the anti-IL-6R monoclonal antibody tocilizumab on immune cell profiles in patients with NMOSD. The researchers administered monthly IV injections of TCZ (8 mg/kg) as an add-on therapy to 19 anti-aquaporin 4 (AQP4)-IgG-positive patients, who had been refractory to corticosteroids and immunosuppressive drugs. The authors collected peripheral blood from patients before and 12 months after infusion of TCZ and obtained 12 health control (HCs) samples as well. Authors noted that only 7 patients provided whole blood samples for gene expression profiles. Overall, the researchers compared patients with NMOSD and HCs, and between before and after the TCZ treatment.

“It is conceivable that effects of tocilizumab on the regulatory lymphocytes could tighten the regulatory immune network for prevention of relapse, which may explain the delayed effect of this type of therapy, “ Yamamura, also the director of the department of immunology and Multiple Sclerosis Center at the National Institute of Neuroscience National Institute of Neuroscience, National Center of Neurology and Psychiatry, in Tokyo, Japan, and colleagues noted.1 “It is possible that before regulatory cells are sufficiently recovered, tapering of concomitant drugs should be conducted at a reasonably slow pace. “In the gene expression analysis, findings showed that neutrophil granule-related genes, predominated by those related to azurophil granules, were significantly upregulated in patients with NMOSD. Authors noted that these genes are usually transcribed in the early developmental stage of neutrophils.2,3 Although investigators did not observe such alterations suggestive of accelerated myeloid turnover 1 year after therapy, they observed effects of tocilizumab on some neutrophil genes as early as 5 days after starting treatment. Additionally, a vitro analysis revealed impairment of naïve T-cell division in patients before infusion and a full recovery after 18 months of therapy.

“In the new era, we have multiple therapeutic choices for NMOSD, requiring the construction of a strategy depending on each person's pathophysiology,” Yamamura et al noted.1 “We believe that our data would contribute to further understanding of the pathogenesis of NMOSD and to inventing a new strategy aiming at the cure and full recovery of the disease.”

REFERENCES
1. Matsuoka T, Araki M, Lin Y, et al. Long-term Effects of IL-6 Receptor Blockade Therapy on Regulatory Lymphocytes and Neutrophils in Neuromyelitis Optica Spectrum Disorder. Neurol Neuroimmunol Neuroinflamm. 2023;11(1):e200173. Published 2023 Oct 20. doi:10.1212/NXI.0000000000200173
2. Theilgaard-Mönch K, Jacobsen LC, Borup R, et al. The transcriptional program of terminal granulocytic differentiation. Blood. 2005;105(4):1785-1796. doi:10.1182/blood-2004-08-3346
3. Evrard M, Kwok IWH, Chong SZ, et al. Developmental Analysis of Bone Marrow Neutrophils Reveals Populations Specialized in Expansion, Trafficking, and Effector Functions. Immunity. 2018;48(2):364-379.e8. doi:10.1016/j.immuni.2018.02.002
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