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Berthele, A.; Giglhuber, K. Neuromyelitis Optica Spectrum Disorders Therapy. Encyclopedia. Available online: (accessed on 24 June 2024).
Berthele A, Giglhuber K. Neuromyelitis Optica Spectrum Disorders Therapy. Encyclopedia. Available at: Accessed June 24, 2024.
Berthele, Achim, Katrin Giglhuber. "Neuromyelitis Optica Spectrum Disorders Therapy" Encyclopedia, (accessed June 24, 2024).
Berthele, A., & Giglhuber, K. (2022, April 22). Neuromyelitis Optica Spectrum Disorders Therapy. In Encyclopedia.
Berthele, Achim and Katrin Giglhuber. "Neuromyelitis Optica Spectrum Disorders Therapy." Encyclopedia. Web. 22 April, 2022.
Neuromyelitis Optica Spectrum Disorders Therapy

Neuromyelitis optica spectrum disorders (NMOSD) are rare neurologic autoimmune diseases that have a poor prognosis if left untreated. For many years, generic oral immunosuppressants and repurposed monoclonal antibodies that target the interleukin-6 pathway or B cells were the mainstays of drug treatment. Recently, these drug treatments have been complemented by new biologics developed and approved specifically for NMOSD. In principle, all of these drugs are effective, but treatment recommendations that take this into account are still pending. Instead, the choice of a drug may depend on other criteria such as drug safety or tolerability.

neuromyelitis optica spectrum diseases immunosuppressants rituximab tocilizumab eculizumab

1. Introduction

Neuromyelitis optica spectrum disorders (NMOSD) are rare chronic inflammatory diseases of the central nervous system (CNS) that, in recent years, were distinguished from the much more common disease multiple sclerosis (MS) [1]. In the classic form of “neuromyelitis optica” (NMO), the disease is characterised by myelitis or optic neuritis that occur sequentially or coincide. In 2004, an autoantibody against the water channel aquaporin 4 (AQP4) was discovered as a cause of NMO and can be detected in the majority of sufferers [2][3], but possibly not all. This autoantibody is diagnostic and has also shown that several other regions of the CNS may also be affected. Antibodies to AQP4, therefore, define a spectrum of possible disease manifestations, merged under the term NMOSD. Additionally, patients with autoantibodies against MOG (myelin oligodendrocyte glycoprotein) may phenotypically resemble AQP4-antibody-positive NMOSD but differ in course and response to immunomodulatory therapies. Therefore, neuromyelitis optica with evidence of MOG antibodies is currently regarded as another, but separate, entity belonging to the MOG-antibody associated diseases (MOGAD) [4].
Data on the epidemiology of NMOSD are still scarce. Worldwide, women prevail over men, but the prevalence varies widely by geographic region and ethnicity. However, with a prevalence of approximately 0.5 to 10 per 100,000 individuals [1], NMOSD is a rare disease according to the WHO’s definition.
NMOSD has a relapsing course, and recovery from relapses is often incomplete [3]. Because patients often develop significant neurological disabilities early on, the disease can be devastating. Therefore, preventive treatment is a significant medical need.
IgG antibodies against AQP4 play a central role in the pathogenesis of NMOSD [5]. They bind to AQP4 expressed on astrocytes in the CNS, activate the complement system, and trigger the formation of the membrane attack complex, eventually leading to astrocytic and neuronal damage.

2. Neuromyelitis Optica Spectrum Disease: Diagnosis and Treatment

In 2015, an international panel of experts agreed on diagnostic criteria for NMOSD, which not only relied on antibody status but also on a set of core clinical symptoms and magnetic resonance imaging (MRI) findings [6]. The diagnosis of antibody negative NMOSD has remained possible. Especially from a therapeutic point of view, this leads to three categories: AQP4-antibody-positive NMOSD, AQP4-antibody-negative NMOSD, and NMOSD attributable to other disease entities (e.g., MOGAD, Sjögren’s syndrome, or other rheumatic diseases).
For many years, drug therapy for NMOSD was mainly empirical using classical immunosuppressants or therapeutic antibodies targeting CD20 or IL-6. Randomised controlled trials (RCTs) on the efficacy of these drugs were not available, and therefore off-label use has occurred. Corticosteroids, azathioprine, mycophenolate mofetil, and rituximab have been recommended as first-line therapies with reasonable success [1]. In the search for more effective and targeted treatment options for NMOSD and thanks to the orphan drug status, three therapeutic antibodies with differing targets, eculizumab, satralizumab, and inebilizumab have been investigated and approved in recent years [7]. In 2019, the positive phase 3 study of the terminal complement inhibitor eculizumab was published, which was subsequently approved as the first disease-modifying drug for AQP4-antibody-positive NMOSD worldwide. Successful phase 3 trials on satralizumab and inebilizumab followed soon after. Satralizumab was approved by the FDA in 2020 and by the European Commission in 2021 for the treatment of AQP4-antibody-positive NMOSD; inebilizumab was approved by the FDA in 2020 and by the European Commission in 2022 for the same indication.
Now that these new drugs are fully available and all three are unequivocally efficacious, treatment recommendations should ideally rely on comparative data. Unfortunately, concerning treatment efficacy, these data are not available, in the sense that no head-to-head trials have been conducted. Instead, the individual risk of treatment may come to the forefront.
Data were gathered from several sources. Firstly, researchers searched PubMed for the respective drugs in conjunction with neuromyelitis optica or NMOSD as title keywords in any type of publications of the last five years. Secondly, researchers analysed the FDA approved drug information leaflets and consulted for any recent safety notifications. In addition, for adverse events of special interest (e.g., PML), separate PubMed search queries were performed.

3. Classical Immunosuppressive Drugs

3.1. Azathioprine

Azathioprine is a prodrug of 6-mercaptopurine and an immunosuppressive antimetabolite. There are single centre reports on azathioprine in NMOSD with up to 103 patients and two meta-analyses covering 977 and 1016 patients [8][9][10][11][12]. Higher case numbers on adverse events (AEs) have been derived from other indications, in particular, inflammatory bowel disease, rheumatoid arthritis (RA), and the early days of kidney transplantation [13][14][15].
According to the official product information approved by the FDA, the frequency and severity of AEs strongly depend on dosing and duration of the treatment, concomitant therapies, and the underlying morbidity [16].
The most common side effects of azathioprine are hematologic and gastrointestinal. Leukopenia or thrombocytopenia can occur at any point during therapy. In NMOSD, leukopenia is reported in around 13% of patients receiving azathioprine [12]. The FDA product information on Imuran® states numbers of >50% for renal homograft patients and 28% of patients with RA [16]. Dose reduction or temporary withdrawal may reverse these effects. However, infections may occur as secondary side effects. In addition, severe leukopenia <2500 cells/mm3, anaemia, and thrombocytopenia have been reported [8][9][10]. Patients with deficiencies of the thiopurine S-methyl transferase (TPMT) or the nucleotide diphosphatase (NUDT15), which are both essential enzymes within the inactivation route of azathioprine, are at special risk of severe myelotoxicity [16]. Regarding gastrointestinal side effects, nausea and vomiting frequently occur within the first months of treatment, the percentage in NMOSD patients ranges from 0.8% to 19% [8][9][10][12]. In some cases, these symptoms come with diarrhoea, fever, or myalgias. Administering the drug after meals or dividing drug doses may reduce gastric irritations. Furthermore, up to 23.5% of NMOSD patients treated with azathioprine develop elevated serum alkaline phosphatase, bilirubin, and/or serum transaminases as signs of hepatotoxicity [10]. Other side effects of low frequency include skin rashes, alopecia, arthralgia, steatorrhea, negative nitrogen balance, reversible interstitial pneumonitis, and Sweet’s syndrome [16].
Apart from these AEs, azathioprine also comes with risks of secondary infection and malignancy. However, the descriptions of serious infections in NMOSD patients under azathioprine treatment are rare. Elsone et al. reported three cases of respiratory infections (out of 103 patients, corresponding to 2.9%), Gomes et al. reported on one patient with tuberculosis (out of 19, 5.3%) [9][11]. In inflammatory bowel disease, the reported infection rates range from 2% to 42% [13]. Occasionally, reactivations of latent infections may be severe or even fatal. There are reports of progressive multifocal leukoencephalopathy (PML) by JC virus infection under treatment with azathioprine [17]; however, most of these patients have been treated with other immunosuppressants as well. Notably, one NMOSD patient with PML under monotherapy with azathioprine has been described [18].
Regarding the risk of secondary malignancies, the data suggest that it is elevated under azathioprine therapy, however, much more after renal transplantation than in other diseases [19]. Yet, there is a controversy on the causality, as the numbers vary strongly between morbidities, and autoimmune diseases themselves may contribute to an elevated malignancy risk. Regarding RA, the FDA states that “it has not been possible to define the precise risk of malignancy” in patients treated with azathioprine [16]. Regarding NMOSD, Costanzi et al. reported three lymphoma cases in 99 patients treated with azathioprine [8]. Gomes et al. observed one case of breast cancer (out of 19 patients) [11]. One large review on patients with inflammatory bowel disease found cancer in 7 out of 3931 patients treated with azathioprine, among them two fatal cases with Hodgkin’s and hepatosplenic lymphoma [13].

3.2. Mycophenolate Mofetil

Mycophenolate mofetil (MMF) also belongs to the drug class of immunosuppressive antimetabolites. The FDA product information is based on five studies that examined the use of MMF in around 1500 transplant patients to prevent organ rejection. In these, “the most common adverse reactions in clinical trials (20% or greater) include diarrhoea, leukopenia, infection, vomiting, and there is evidence of a higher frequency of certain types of infections, for example, opportunistic infection” [20].
Regarding the use in NMOSD, there has been one meta-analysis of 11 studies that summarised 106 AEs in 594 patients, corresponding to a rate of 17.8% [21]. The largest proportion of data was derived from Huang et al. with 90 patients, of which 43% of the patients developed adverse events [22]. Interestingly, the observed rate varied considerably. One study reported only 3 out of 62 patients with mild AEs, namely mild hair loss and mild liver enzyme elevations [23]. Considering the pooled data of Songwisit, the most common AEs in NMOSD were infections in 33/594 patients [21]. The leading infections were respiratory infections and pneumonia, followed by urinary tract and herpes zoster infections. Huang reported that 3 out of 21 infections were severe, i.e., two patients suffering from pneumonia of unreported aetiology needed ventilation and one patient developed a hemorrhagic varicella infection three months after MMF initiation and died from respiratory distress syndrome [22]. To the best of researchers knowledge, there were no other cases of serious viral infections such as, for example, JCV-associated PML, cytomegalovirus infections, or viral reactivation with Hepatitis B or C [21][24].
The next most frequent side effects were gastrointestinal, including elevated liver enzymes in 4.5–20% of patients, diarrhoea and other digestive complaints in approximately 2% of patients [21][22][25]. In other indications, gastrointestinal bleeding requiring hospitalisation, ulcerations, and perforations were also observed in clinical trials [20]. Bone marrow suppression was observed in 0.9–2.7% of NMOSD patients treated with MMF and included foremost anaemia and leukopenia [21][22]. The symptoms and laboratory abnormalities were mostly reversible after discontinuation of treatment. Considering quality of life and wellbeing, mild hair loss in around 2% of patients is an issue [21][22]. Interestingly, Huang et al. showed, by means of regression analysis, that adverse events of MMF therapy significantly decreased in combination with glucocorticoids [22].
Like azathioprine, MMF for immunosuppression has been shown to increase the risk of developing malignancies, especially lymphomas or skin cancer [20]. Huang et al. reported one case of rectal cancer discovered by elevated levels of the carcinoembryonic antigen during MMF therapy in a patient with NMOSD [22]. Poupart et al. described one fatal case of lung cancer in an NMOSD patient with a smoking history and six years of MMF treatment [24]. Causalities could not be proven in both cases.

4. Rituximab

Rituximab is a monoclonal antibody against CD20. It is approved for the treatment of non-Hodgkin lymphoma, chronic lymphocytic leukemia, RA, granulomatosis with polyangiitis, microscopic polyangiitis, and pemphigus vulgaris. Regarding RA, there are data from clinical studies on >2500 patients. “Very common” adverse events (at least 1/10 of patients treated) were infections of the upper respiratory and the urinary tract, infusion-related reactions (IRR), headache, and reduced serum levels of IgM [26].
Regarding NMOSD, there are several meta-analyses available, which slightly differ regarding the trials selected [27][28][29][30]. The meta-analyses all covered the study of Kim et al. [31], which has been the largest open-label trial with 100 patients included. Additionally, there have been two randomised controlled trials. Nikoo et al. compared rituximab with azathioprine [32] in terms of efficacy, and the RIN-1 study by Tahara et al. compared rituximab with a placebo [33]. Only recently, the Canadian Agency for Drugs and Technologies in Health (CADTH) published a Health Technology Report on rituximab in NMOSD, which covered safety as well [34].
Depending on the depth of data collection, the share of patients with AEs was reported to be 16.46% [29] up to 28.57% [30]. Most common were IRR in 10–13% of patients and infections in around 9% of patients [28][32]. Interestingly, the RIN-1 study observed AEs in 17/19 patients, i.e., in 90% [26]. Most of them were mild and infusion related. From the RA studies, it has been reported that IRR most often occurred after the first administration of rituximab, and premedication with glucocorticoids alleviated frequency and severity [26].
Infections mainly involve upper respiratory tract and urinary tract infections. Additionally, there is a risk of reactivating opportunistic infections such as herpetic rash and tuberculosis [27]. In RA, there have been reports of fatal PML under therapy with rituximab [35]; however, in NMOSD, to the best of researchers knowledge, there are as yet none. Severe infectious AEs have occurred in 2–3% of patients, among them severe pneumonia, septicemia, and severe allergic reactions [29][32]. Again, Tahara et al. [33] reported much higher percentages with severe adverse reactions in 3/19 patients (16%). However, apart from one adverse reaction (an infection of the foot not further classified), the listed severe events (lumbar compression fracture, diplopia, and uterine cancer) may count among very rare or even unrelated side effects [33].
Interestingly, there are data on treatment-related mortality. Mortality was reported in one review with 1.6% without further clarification of the causes of death [28]. A second review reported that 5/577 (0.9%) of NMOSD patients treated with rituximab died, of whom two patients suffered from pneumonia, one patient suffered from a urogenital infection and thrombosis, one patient died after bone marrow transplantation, and one patient died of cardiac and respiratory failure due to severe myelitis with rostral extension [29]. A third review reported one death by septicemia and one death after cardiovascular failure [27][36][37]. Touching upon the latter, for RA, severe cardiovascular events were reported to be equally frequent in patients receiving rituximab or a placebo [26].
Further generic but important side effects of rituximab treatment include neutropenia, mainly mild to moderate, and low serum titers of IgG and IgM, at least over time. Hypogammaglobulinemia, however, is still debated as to whether and how it correlates with an increased risk of any or severe infections [26][38].

5. Tocilizumab

Tocilizumab is a monoclonal antibody against the interleukin-6 receptor that is approved to treat several rheumatic disorders, including RA. The FDA approved product information on tocilizumab makes use of data derived from five studies with more than 4000 patients [39]. Among these, only 288 patients received tocilizumab as a monotherapy, whereas the majority was on a combination with, for example, methotrexate. The most-reported AEs were upper respiratory tract infections, nasopharyngitis, headache, hypertension, and increased transaminase levels. Serious AEs primarily comprised infections, including pneumonia, urinary tract infections, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis, and bacterial arthritis. Moreover, the product information points to opportunistic infections such as tuberculosis, cryptococcosis, aspergillosis, candidiasis, and pneumocystosis which may occur.
Regarding the safety of tocilizumab in NMOSD, there are several case reports and a few case series. However, data are often blended by the concomitant use of other immunosuppressives such as azathioprine or MMF, and the diligence of safety reporting varies [40][41][42][43]. In 2020, Zhang et al. published their results on the TANGO study, the first and only randomised controlled trial on tocilizumab versus azathioprine for the treatment of NMOSD [44]. Two systematic reviews have summarised the available data in NMOSD [45][46]. Lotan et al. described that 11 out of 17 studies reported no AEs. In the remaining studies, leukopenia, elevated cholesterol levels, urinary tract infections, and anaemia were the foremost AEs [45]. Xie et al. described 75 AEs in a total of 89 patients, including the TANGO trial (84%), which contributed 36 treatment-related AEs in 59 patients (61%) [46]. The AEs were mostly mild: 28–29% of patients developed urinary tract infections, 21–29% of patients developed upper respiratory tract infections, 24–31% of patients developed mild liver enzyme elevations, and 6–10% of patients developed elevated cholesterol levels or leuko-/lymphopenia [44][46].
Of note, in a case series of 57 NMOSD or MOGAD patients treated with tocilizumab for a median of two years, pneumonia was more frequent in patients with add-on immunosuppressants (18% versus 6% of patients under tocilizumab monotherapy). Four patients suffered a flare-up of concomitant autoimmune diseases [43].
In the TANGO trial, five SAEs occurred (in 59 patients = 8%), including severe pneumonia, herpes zoster, deep vein thrombosis, cerebral haemorrhage, and myelitis, none with a fatal outcome. There were two deaths reported, one each under tocilizumab and azathioprine. The two deaths were both classified as not related to treatment, i.e., one as due to “central respiratory failure secondary to myelitis involving the high cervical spine and medulla oblongata”, the other to “severe myelitis” [41][44].
As for secondary malignancies, the FDA product information generally advises that immunosuppressives may increase the risk. However, the specific impact of treatment with tocilizumab is unknown [39], and no cases in tocilizumab-treated NMOSD patients have been reported yet.
Finally, hypersensitivity reactions must be mentioned as a potential risk. Anaphylaxis and other hypersensitivity reactions that required treatment discontinuation were reported in <1.0% for RA, among them fatal cases [39]. For NMOSD and MOGAD, Ringelstein et al. reported infusion-related reactions (headache, abdominal pain, as well as vertigo/nausea) in 7/57 patients treated with tocilizumab [43].

6. Eculizumab

Eculizumab is an IV monoclonal antibody against the complement protein C5, and FDA-approved, since 2019, for treating AQP4-antibody-positive NMOSD. Safety data are available from a small pilot study, the placebo-controlled pivotal trial PREVENT, and its open-label extension (OLE) study [47][48][49].
Summarised data from the latter two studies came from the treatment of 137 AQP4-antibody-positive NMOSD patients for a total of 362.3 patient years (PY) until June 2020 [49]. The rates of treatment-related AEs were similar in the eculizumab group of the PREVENT trial and during the OLE; altogether, there were 183.5 AEs in 100 PY (as compared with 167.5 AEs in 100 PY in the PREVENT placebo arm). Most common AEs were headache (57.7 events in 100 PY), nasopharyngitis (27.6 in 100 PY), upper respiratory tract and urinary tract infection (25.7 each in 100 PY), back pain and diarrhoea (12.4 each in 100 PY), nausea (13.2 in 100 PY), and arthralgia (8.8 in 100 PY). The rate of treatment-related SAEs was 8.0 in 100 PY. SAEs included severe infections, which occurred in 25/137 patients, corresponding to 10.2 events in 100 PY. Among these, five patients suffered from pneumonia, four patients each from urinary tract infection or cholecystitis, and two patients each from cellulitis or sepsis [49].
Interestingly, a subgroup analyses of the PREVENT double-blind phase revealed that serious infections occurred less frequently with eculizumab than with a placebo, regardless of concomitant immunosuppressive medications or prior rituximab use [50]. There was one reported death in the PREVENT trial; the patient died under medication with eculizumab and azathioprine due to pleural empyema [47]. The event was categorised as possibly related to eculizumab treatment. During the OLE, no fatalities were reported.
Eculizumab is known to especially increase the risk of infections with encapsulated bacteria such as meningococci. The risk has been estimated to be 2000-fold higher than in the untreated population [51]. There have been reports of meningococcal infections despite proper vaccination, hereunder one NMOSD patient in the pilot study with eculizumab [48][52]. Neither the PREVENT study nor the OLE observed meningococcal infections. However, one patient in the OLE developed an infection due to Neisseria gonorrhoeae [49].
Furthermore, the FDA product information of Soliris® warns of infections by Aspergillus species [51]. These are reported in patients with atypical hemolytic uremic syndrome treated with eculizumab, including one fatality due to a ruptured cerebral aneurysm related to Aspergillus infection [53].
Being a therapeutic protein, eculizumab may be prone to trigger infusion-related reactions. Notably, the rate of IRR is rather low, and symptoms are mild and transient. In clinical trials, no patient experienced an infusion-related reaction requiring eculizumab discontinuation [47][51].


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