Giovannelli et al wrote a study comparing the various first-line immunosuppressants used in neuromyelitis optica spectrum disorder (NMOSD). The benefit of this kind of meta-analysis is that it provides us with a bird’s eye view of the main therapeutics used to treat a particular disease and how they perform against each other.

In their meta-analysis, Giovannelli and colleagues compared the efficacy of 3 first-line NMOSD therapies: rituximab, mycophenolate motefil, and azathioprine. These are all immunosuppressants.

The research team characterized NMOSD as “an inflammatory disease of the central nervous system (CNS) that is described as an astrocytopathy leading to the loss of astrocytes associated with extensive tissue damage along with complement deposition and pro-inflammatory cytokine, macrophage, and granulocyte infiltrates.”

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The overarching goal of NMOSD therapies, which rituximab, mycophenolate motefil, and azathioprine share, is to prevent further attacks by suppressing the immune response. 

Read more about NMOSD treatment 

Before Giovannelli and colleagues wrote about their findings, they noted that Huang and colleagues have previously published a similar meta-analysis comparing the same medications and more in their efficacy against NMOSD. Huang et al concluded that rituximab and mycophenolate motefil were superior to azathioprine and that they should be recommended as treatments to avoid relapses. 

However, Giovannelli et al did not agree completely with the methodology of the study (for example, Huang et al used annualized relapse rate as opposed to time to first relapse to determine the efficacy of the drugs tested). Hence, they conducted their own. 

Recommendations Vary With Different Endpoints

The research team conducted a systematic review on clinical studies that considered at least 2 immunosuppressants among rituximab, mycophenolate motefil, and azathioprine in first-line conditions. They carefully reviewed the clinical trials studied, with a fourth author arbitrating any disagreements. 

The inclusion criteria were that the studies must include the hazard ratio (HR) and time to first relapse as parameters of the efficacy of the drugs used. The researchers also made sure to note any detail of significance regarding the studies investigated (study design, sample size, follow-up time, etc); if any information was lacking, they would reach out directly to the authors of the included studies. 

In total, Giovannnelli et al identified 7 studies that matched their inclusion criteria to be included in their meta-review (after a rigorous exclusion process).

Now let’s discuss the results. When rituximab was compared to mycophenolate motefil, the results indicated there was a higher risk of relapse under mycophenolate motefil. When rituximab was compared to azathioprine, results indicated no statistically significant difference in terms of HR; but when using the annualized relapse rate as an indicator, rituximab performed better than azathioprine. There was no statistically significant difference between azathioprine and mycophenolate motefil. 

Read more about NMOSD therapies 

”The results of this updated systematic review and meta-analysis of the most widely used immunosuppressants in first-line strategies for NMO suggest that [rituximab] is more efficient than [mycophenolate motefil] in delaying relapses,” the researchers wrote.

”Even if the results of our meta-analysis cannot conclude that [rituximab] has better efficacy in delaying the first relapse than [azathioprine], the observed effect difference between both treatments combined with the results of previous studies using as outcome the annualized relapse rate may be in favor of [rituximab].”

Giovannelli and colleagues proposed a number of different areas that may be worth exploring by future researchers: 

  • Investigating seronegative NMOSD
  • Evaluating the efficacy of widely-used treatments not included in this study
  • Investigating the public health cost of each treatment. 

Other Immunosuppressive Options 

We have already mentioned there are other immunosuppressive drugs being used to treat NMOSD. Romeo and Segal, in their study on the treatment of neuromyelitis optica spectrum disorder, listed a few: 

  • Eculizumab is a monoclonal antibody that works against terminal complement component 5; it has been approved for use in paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. It was recently approved for use by the FDA for NMOSD. 
  • Tocilizumab is a monoclonal antibody that works against interleukin-6 receptor; it has been approved for use against rheumatoid arthritis and has been recommended for NMOSD. 
  • Bortezomib is an inhibitor of the 26s proteasome and is approved for use against multiple myeloma and mantle cell lymphoma; in an uncontrolled trial involving 5 NMOSD patients it appears effective in reducing relapses. 
  • Hematopoietic stem cell therapy has shown positive results in patients with aggressive relapsing MS and is currently under study for use in NMOSD. 

The list above is a snapshot of the current medications that are being discussed or investigated for use in NMOSD.

Romeo and Segal wrote about where they think NMOSD treatment is heading: “Treatment options are on the verge of expansion. Rigorous, placebo-controlled trials are underway, and the results of some should soon be reported.”

”New modes of B-cell therapy may enter clinical practice,” they added. ”Treatments which disrupt cytokine and complement pathways, as well as cell-based therapies, are being investigated. Randomized active-comparator trials will be needed to help guide treatment selection.”


Huang W, Wang L, Zhang B, et al. Effectiveness and tolerability of immunosuppressants and monoclonal antibodies in preventive treatment of neuromyelitis optica spectrum disorders: A systematic review and network meta-analysis. Mult Scler Relat Disord. 2019;35:246-252. doi:10.1016/j.msard.2019.08.009

Giovannelli J, Ciron J, Cohen M, et al. A meta-analysis comparing first-line immunosuppressants in neuromyelitis optica. Ann Clin Transl Neurol. 2021;8(10):2025-2037. doi:10.1002/acn3.51451

Romeo AR, Segal BM. Treatment of neuromyelitis optica spectrum disorders. Curr Opin Rheumatol. 2019;31(3):250-255. doi:10.1097/BOR.0000000000000603