Abstract
Myelin oligodendrocyte glycoprotein-immunoglobulin G associated disease (MOGAD) is an autoimmune demyelinating disorder of the central nervous system (CNS) which usually occurs with recurrent optic neuritis, transverse myelitis, acute disseminating encephalomyelitis, or brainstem encephalitis. To date, the anti-CD 20 drug rituximab (RTX) is employed in MOGAD although some authors reported the efficacy of Tocilizumab (TCZ) in refractory patients. We present the case of a woman affected by refractory MOGAD who was treated with TCZ after therapy with RTX had failed to prevent relapses. We also conducted a current literature review on TCZ use in MOGAD. A 57-year-old Caucasian woman affected by MOGAD with severe motor impairment and cognitive dysfunction was treated from 2020 to February 2022 with RTX. However, she experienced progressive clinical and cognitive worsening associated with white matter lesions mimicking leukodystrophy. In February 2022, the patient started therapy with TCZ administered with improvement of cognitive performance, walking ability, and brainstem functions. During TCZ, our patient reached the condition of NEDA-3 (no relapse, no increase in disability, no MRI activity on neuroimaging follow-up performed in September 2023). Moreover, the patient experienced paucisymptomatic SARS-CoV-2 infection that did not modify TCZ schedule. To date, there are few evidence on the efficacy and safety of TCZ in MOGAD. However, all the reviewed cases showed that TCZ represents an effective therapy in drug-resistant MOGAD. Our case highlights the efficacy of TCZ in drug resistant MOGAD and strengthens previous reports of TCZ safety and efficacy in MOGAD.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
MOGAD is a demyelinating disease of the CNS with clinical, demographic, and radiological features different from multiple sclerosis (MS) and from aquaporin-4 (AQP4) autoantibody-associated neuromyelitis optica spectrum disorder (NMOSD). MOG is a glycoprotein present in the outer layer of the myelin sheath and on the surfaces of oligodendrocytes, probably with a structural function of adhesion protein. If the AQP4-NMOSD is an example of astrocytopathy, since the AQP4-IgG damage astrocytes, the MOGADs can be considered an example of oligodendrocytopathy [1]. Patients with MOGAD generally have a good response to immunotherapy. Traditional disease-modifying therapies (DMTs) used for MS appear ineffective or even detrimental to treat MOGAD. Immunotherapy for MOGAD includes rituximab (RTX), an anti-CD20 monoclonal antibody, azathioprine, mycophenolate mofetil, and intravenous immunoglobulins [2]. A recent meta-analysis underlined the safety and efficacy profile of RTX for relapse prevention in patients with MOGAD [3]. However, some patients with MOGAD experience a recurrence of clinical relapses and new radiological lesions despite being on RTX therapy. Recently, the efficacy and safety of tocilizumab (TCZ), a humanized antibody directed against the IL-6 receptor, has been documented in several case reports of MOGAD unresponsive to RTX as shown below in Table 1.
Disease pathology is linked to macrophages retrieval, microglial activation, and inflammation mediators like IL-6. IL-6, a pleiotropic cytokine upregulated in MOGAD induction and relapses, causes Th17 lymphocyte differentiation which are responsible for direct demyelination and creates positive feedback for IL-6 release [4]. MOGAD pathogenesis could be only partially supported by complement via classic activation (antibody-MOG binding). NMOSD AQP4 + antigen–antibody binding is monovalent, providing a massive activation of C1q, while in MOGAD a bivalent antibody binding is needed [5]. Hence, complement inactivation therapies did not show encouraging results in patients with MOGAD, in an opposite way to NMOSD AQP4 + individuals. For this reason, TCZ is even more frequently used in MOGAD. TCZ has been also used in complicated SARS-Cov-2 infection with hyperinflammatory syndrome to suppress cytokine release syndrome and to reduce risk for invasive mechanical ventilation or mortality. In this article, we reported the case of a relapsing MOGAD characterized by the accumulation of confluent and bilateral hemispheric lesions related to recurrent episodes of encephalitis resulting in a final radiological picture resembling a leukodystrophy pattern, refractory to anti-CD-20 therapy, who later experienced SARS-CoV-2 infection during TCZ treatment. We also reviewed and updated the existing evidence up to October 2023 on the use of TCZ in patients with MOGAD (Fig. 1).
Clinical scenario
In 2017, a 56-year-old Caucasian woman presented with a history of recurrent episodes of visual loss, diplopia, and gait abnormality initially followed by full recovery. Clinical examination showed brisk tendon reflexes in both lower and upper limbs as well as nystagmus and mild ataxia with a calculated EDSS of 2.0. The patient underwent lumbar puncture and brain MRI with gadolinium administration that resulted, respectively, in the absence of oligoclonal bands and bilateral demyelinating lesions of frontal, temporal, parietal white matter, and other lesions in the cerebellum, midbrain, at the level of the cerebellar peduncles, at the bulbar-medullary junction, and in the medulla at the level of D5 (Fig. 2). Conus medullaris involvement nor perineural optic sheath enhancement was reported at that time. Given the relapsing–remitting course and the findings at brain MRI, a MS diagnosis was initially made. The patient started therapy with interferon-beta-1a until July 2018, when she presented a new relapse characterized by diplopia and postural imbalance. Then, the patient started natalizumab treatment until July 2019 when she presented with severe cognitive impairment (i.e., executive functions, verbal memory, and reduced verbal fluency, spatial and temporal disorientation) and limb ataxia together with severe motor impairment. A new lumbar puncture was performed for the suspicion of progressive multi-focal leukoencephalopathy (PML), giving negative results in July 2019 and the same was repeated in October 2019 with a consistent result. A new brain MRI revealed confluent demyelinating lesions involving the parietal, temporal, and occipital white matter, some of them showing a patchy gadolinium enhancement. A MOGAD encephalitis was at that time confirmed after the presence of anti-MOG antibodies had been shown by a fixed cell-based assay in December 2019 and in March 2020. The patient underwent plasma exchange therapy after steroid therapy had failed, without significant clinical improvement. A new brain MRI showed a widespread leukoencephalopathy pattern with a post-contrast T1-weighted imaging enhancement. For this reason, in April 2020, the patient started therapy with RTX 1000 mg every 2 weeks followed by new courses every 6 months. Meanwhile, the patient became unable to walk and showed severe dysphagia and further progressive worsening of the cognitive dysfunction being unable to perform any cognitive assessment. In January 2022, there was a sudden symptom worsening with spatial agnosia, prosopagnosia, and pseudobulbar syndrome. She was admitted again to our clinic and submitted to a new course of plasma exchange, with no significant clinical improvement. A new brain MRI (Fig. 3) showed a further increase in the lesion burden both at the brain and brainstem level. Thus, in February 2022, therapy with TCZ was started at the dosing of 8 mg/kg every 4 weeks (weight 40 kg; total dose: 320 mg per infusion). IL-6 levels determined before starting therapy were 15 pg/mL (normal value < 7 pg/mL). The infusions were well tolerated; no adverse events or life-threatening conditions were reported. On April 25, 2022, despite being fully vaccinated (three doses), the patient tested positive for SARS-CoV-2 and reported fever, cough, and dyspnea. She underwent therapy with nirmatrelvir/ritonavir obtaining a dramatic regression of all symptoms in about 24 h. COVID-19 negativity was documented by a negative test for SARS-CoV-2 on May 7, 2022, and the new TCZ course was administered on May 30th. Before this administration, new IL-6 dosing showed a reduction to 4 pg/mL. During observation until January 2023, infusions of TCZ have been administered without observing new clinical events or adverse effects. In the last clinical examination, we documented on the contrary a moderate recovery of cognitive function (MMSE = 15) and walking capacity, being the patient able to walk with bilateral assistance. Family members and the caregiver of the patient confirmed the significant improvement of general conditions; the patient is actually able to assume lunches and to drink autonomously. A new MRI of the brain performed in October 2022 showed a reduction of the lesion load at the level of the middle cerebellar peduncle and the right middle-superior frontal gyrus in the absence of gadolinium-positive lesions or new T2 lesions (Fig. 3). In February 2023, a subcutaneous catch port was inserted. However, in April 2023, the patient was hospitalized for a Pseudomonas aeruginosa infection of the “port-a-cath,” treated with piperacilline-tazobactam therapy and removing of the port-a-cath. On May 5th, the patient was tested positive for Sars-Cov-2 and treated with remdesivir. The patient also received her scheduled administration of TCZ on May 11, 2023, during the hospitalization. In July 2023, the route of administration of TCZ was changed to a subcutaneous route at a dosage of 162 mg every two other weeks. She received six subcutaneous administrations at the date of the last follow-up up to October. At the end of September 2023, a new MRI was repeated showing no increase in lesion load (Fig. 3). At the date of the last follow-up in October 2023, no new relapse or signs of disease progression have been documented.
Discussion
The patient we described showed a severe pattern of leukodystrophy-like/leukoencephalopathy MOGAD unresponsive to RTX treatment who on the contrary appears to improve after TCZ therapy. In this case, TCZ was associated with a favorable safety and efficacy profile, even in the presence of COVID-19.
Previous case reports support the efficacy and safety of TCZ in patients with MOGAD unresponsive to RTX or other therapies. Twenty-three patients have been previously described receiving RTX therapy alone or other treatments. The most numerous groups of patients were that of Ringelstein and colleagues who evaluated the efficacy and long-term safety of TCZ treatment in 14 patients with MOGAD, 36 with seropositive AQP4-IgG, and 7 with seronegative NMOSD. The observation period was 23.8 months. Their analysis showed that 79% of patients with MOGAD did not have relapses during TCZ treatment. The percentage of patients with absence of relapses was higher in MOGAD patients than in patients with seropositive and seronegative NMSOD AQP4-IgG [6]. Table 1 reports all the published cases supporting the efficacy and safety of TCZ in patients with MOGAD.
Of the reported twenty-five cases, including the one described by us, men represent 48% (n = 12) of patients and women 52% (n = 13). The median age at the time of TCZ initiation was 44.3 years, and the median observation period was 20.8 months. Adverse events associated with TZC therapy were observed only in two of them. A man developed a dental infection and a woman the occurrence of TCZ-related hypertriglyceridemia needing a statin prescription. We did not observe any therapy-related adverse events in our patient. Just 4 (16%), out of the 25 patients examined, presented new relapses during therapy with TCZ, and MRI disease activity was detected just in one patient (4%) [6]. No clinical relapses or appearance of further radiological lesions were observed in our patient during treatment with TCZ. Furthermore, the follow-up MRI performed in October 2022 as abovementioned showed instead an improvement in the lesion load.
The patient reported by us had previously also used interferon-beta and natalizumab due to the former diagnosis of MS. During the treatment with these therapies as well as during RTX therapy, she continued to experience relapses and a marked worsening of clinical conditions. This is analogous with other case reports that have noted a worsening of the disease in patients with AQP4 + NMOSD receiving DMTs classically used to treat MS such as beta-interferons, fingolimod, and in particular natalizumab, with accumulation of disability and disease progression [14,15,16]. Kleiter and colleagues suggested testing for anti-AQP4 and anti-MOG antibodies in patients diagnosed with MS before initiating natalizumab therapy, although a percentage of patients with NMOSD could be seronegative. They also proposed that in patients not responding to natalizumab, in addition to PML or the presence of neutralizing antibodies or even to the possibility of a relapse, a missed diagnosis of NMOSD should be considered [16]. It is unknown the mechanism or the mechanisms leading to worsening of MOGAD during natalizumab. An hypothesis could be the increase in the number of antibodies-producing plasma cells. In fact, natalizumab induces an increase in the numbers of peripheral B cells and CD138 + plasma cells, which in turn might increase the title of anti-MOG-antibodies that correlate with the severity of the disease. This mechanism had already been hypothesized by other authors [16] for patients with AQP4 + NMO who worsened during therapy with natalizumab. Radiological phenotypes of MOGAD are various and heterogeneous. In our patient, accumulation of lesions over time resulted in a final radiological picture mimicking that of a leukodystrophy. Leukodystrophy-like lesions are one possible presentation of MOGAD. These are very rare forms, typical of the progressive forms of MOGAD and described in pediatric patients, are associated with a poor prognosis, severe cognitive impairment, and psychiatric manifestations, and are also characterized by a poor response to common immunotherapies. In 2018, Hacohen and colleagues reported a leukodystrophy-like MRI pattern in seven pediatric MOGAD patients younger than 7 years of age [17]. Similar case reports were reported exclusively in children until in 2021, when Wang and collaborators observed a leukodystrophy-like pattern also in two adult patients with MOGAD [18]. We identified some differences between Hacohen’s pediatric cases, Wang’s two adult patients, and the adult patient we reported. Pediatric patients in Hacohen’s study had acute/subacute onset with rapid symptom progression and had a distinct clinical benefit from steroids. Contrast enhancement was observed in leukodystrophy-like lesions on MRI; differently, the two adult patients in Wang’s study experienced a chronically progressive course with no acute attacks, no benefit from steroids, and no contrast enhancement in leukodystrophy-like lesions. Finally, our patient had an acute onset of cognitive, motor, and ataxic symptoms after 11 infusions of natalizumab, developing a rapidly progressive form of dementia with subsequent slow progression of cognitive symptoms, alternating subacute phases of relapses. She did not benefit from steroids like Wang’s adult patients and occasionally had contrast enhancement in leukodystrophy-like lesions similarly to the pediatric patients.
In leukodystrophy-MOGAD, a differential diagnosis between MOGAD and leukodystrophy could be challenging. The confirmed presence of anti-MOG antibodies, especially if determinate by a cell-based assay, a history of recurrent optic neuritis, progressive cognitive and psychiatric manifestations, observation of spinal cord lesions, absence of positive familiar history, and genetic screening with negative results for leukodystrophies when necessary, is elements in favor of MOGAD. Moreover, our MRIs documented lesions of cortical regions and subcortical U-fibers, areas usually preserved in patients with leukodystrophies [19, 20].
TCZ was found to be safely administered also in the occurrence of a SARS-Cov-2 infection according to previous reports indicating how both in MOGAD and during COVID-19 there is an increase in pro-inflammatory cytokines including IL-6. Elevated levels of IL-6, expression of the cytokine release syndrome, are associated with a complicated and severe course of COVID-19 [21]. In fact, IL-6 promotes pulmonary fibrosis and respiratory dysfunction and can also inducer intrarenal inflammation, myocardial fibrosis, and kidney and gastrointestinal damage. The 8 mg/kg TCZ dosage used to treat COVID-19 pneumonia is the same administered to treat MOGAD [22, 23]. Therefore, it appears evident that treatment with TZC since it acts on a common target to the pathogenesis of COVID-19 and MOGAD, as suggested by an analogous previous case report [10], should not be stopped in case of SARS-Cov-2 infection and can be considered safe.
Conclusion
A recurrent and refractory to therapy MOGAD can result in a radiological leukodystrophy-like/leukoencephalopathy pattern with poor outcome and low response to the common immunotherapies. TCZ can be considered an effective therapy for the treatment of these forms of MOGAD. Moreover, we reported for the first time in a patient with MOGAD a worsening of the disease during the treatment with natalizumab that showed ineffectiveness to prevent relapses. Finally, TCZ can also be considered a safe therapy, with no need for a modified schedule during Sars-Cov-2 infection.
References
Mader S, Kümpfel T, Meinl E (2020) Novel insights into pathophysiology and therapeutic possibilities reveal further differences between AQP4-IgG- and MOG-IgG-associated diseases. Curr Opin Neurol 33(3):362–371. https://doi.org/10.1097/WCO.0000000000000813
Chen JJ, Eoin P, Flanagan M, Bhatti T, Jitprapaikulsan J, Dubey D, Alfonso S, Chiriboga L, Fryer JP et al (2020) Steroid-sparing maintenance immunotherapy for MOG-IgG associated disorder. Neurology 95(2):e111. https://doi.org/10.1212/WNL.0000000000009758
Nepal G, Kharel S, Coghlan MA, Rayamajhi P, Ojha R (2022) Safety and efficacy of rituximab for relapse prevention in myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG)-Associated Disorders (MOGAD): A Systematic Review and Meta-Analysis. J Neuroimmunol 364. https://doi.org/10.1016/j.jneuroim.2022.577812
Rothaug M, Becker-Pauly C, Rose-John S(2016) The role of interleukin-6 signaling in nervous tissue, Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Volume 1863, Issue 6, Part A, Pages 1218-1227.https://doi.org/10.1016/j.bbamcr.2016.03.018 (ISSN 0167-4889)
Marignier R, Yael Hacohen Y, Cobo-Calvow A et al (2021) Myelin-oligodendrocyte glycoprotein antibody-associated disease. Lancet Neurol 20(9):762–772. https://doi.org/10.1016/S1474-4422(21)00218-0
Ringelstein M, Ayzenberg I, Lindenblatt G, Fischer K, Gahlen A, Novi G, Hayward-Könnecke H, Schippling S, Rommer PS, Kornek B, Zrzavy T, Biotti D, Ciron J, Audoin B, Berthele A, Giglhuber K, Zephir H, Kümpfel T, Berger R, Röther J, Häußler V, Stellmann JP, Whittam D, Jacob A, Kraemer M, Gueguen A, Deschamps R, Bayas A, Hümmert MW, Trebst C, Haarmann A, Jarius S, Wildemann B, Grothe M, Siebert N, Ruprecht K, Paul F, Collongues N, Marignier R, Levy M, Karenfort M, Deppe M, Albrecht P, Hellwig K, Gold R, Hartung HP, Meuth SG, Kleiter I, Aktas O (2021) Neuromyelitis Optica Study Group (NEMOS). Neurol Neuroimmunol Neuroinflamm 9(1):e1100. https://doi.org/10.1212/NXI.0000000000001100
Novi G, Gastaldi M, Franciotta D, Pesce G, Benedetti L, Uccelli A (2019) Tocilizumab in MOG-antibody spectrum disorder: a case report. Mult Scler Relat Disord 27:312–314. https://doi.org/10.1016/j.msard.2018.11.012
Hayward-Koennecke Helen, Reindl Markus, Martin Roland, Schippling Sven (2019) Tocilizumab treatment in severe recurrent anti-MOG-associated optic neuritis. Neurology 92(16):765–767. https://doi.org/10.1212/WNL.0000000000007312
Rigal J, Pugnet G, Ciron J, Lépine Z, Biotti D (2020) Off-label use of tocilizumab in neuromyelitis optica spectrum disorders and MOG-antibody-associated diseases: a case-series. Mult Scler Relat Disord 46. https://doi.org/10.1016/j.msard.2020.102483
Masuccio FG, Lo Re M, Bertolotto A, Capobianco M, Solaro C (2020) Benign SARS-CoV-2 infection in MOG-antibodies associated disorder during tocilizumab treatment. Mult Scler Relat Disord 46. https://doi.org/10.1016/J.MSARD.2020.102592
Elsbernd PM, Hoffman WR, Carter JL, Wingerchuk DM (2021) Interleukin-6 inhibition with tocilizumab for relapsing MOG-IgG associated disorder (MOGAD): a case-series and review. Mult Scler Relat Disord 48. https://doi.org/10.1016/J.MSARD.2020.102696
Escolà JK, Deuschl C, Junker A, Dusse F, Pul R, Kleinschnitz C, Köhrmann M, Frank B (2022) MOG antibody–associated encephalomyelitis mimicking bacterial following ChAdOx1 NCoV-19 vaccination: a case. Ther Adv Neurol Disord 15. https://doi.org/10.1177/17562864211070684
Nagahata K, Suzuki S, Yokochi R, Nei Y, Hagino N (2022) “Recurrent optic perineuritis with myelin oligodendrocyte glycoprotein antibody-associated disease complicated with granulomatous polyangiitis.” Cureus 14(5). https://doi.org/10.7759/CUREUS.25239
Jacob A, Hutchinson M, Elsone L, Kelly S, Ali R, Saukans I, Tubridy N, Boggild M (2012) Does natalizumab therapy worsen neuromyelitis optica? Neurology 79(10):1065–1066. https://doi.org/10.1212/WNL.0B013E31826845FE
Palace J, Leite MI, Nairne A, Vincent A (2010) Interferon beta treatment in neuromyelitis optica: increase in relapses and aquaporin 4 antibody titers. Arch Neurol 67(8):1016–1017. https://doi.org/10.1001/ARCHNEUROL.2010.188
Kleiter I, Hellwig K, Berthele A, Kümpfel T, Linker RA, Hartung HP, Paul F, Aktas O (2012) Failure of natalizumab to prevent relapses in neuromyelitis optica. Arch Neurol 69(2):239–245. https://doi.org/10.1001/ARCHNEUROL.2011.216
Hacohen Y, Rossor T, Mankad K, Chong Wk, Lux A, Wassmer E, Lim M, Barkhof F, Ciccarelli O, Hemingway C (2018) ‘Leukodystrophy-like’ phenotype in children with myelin oligodendrocyte glycoprotein antibody-associated disease. Dev Med Child Neurol 60(4):417–23. https://doi.org/10.1111/DMCN.13649
Wang J, Qiu Z, Li D, Yang X, Ding Y, Gao L, Liu A et al (2021) Clinical and imaging features of patients with encephalitic symptoms and myelin oligodendrocyte glycoprotein antibodies. Front Immunol 12:3912. https://doi.org/10.3389/FIMMU.2021.722404/BIBTEX
Eldridge R, Anayiotos CP, Schlesinger S, Cowen D, Bever C, Patronas N, McFarland H (1984) Hereditary adult-onset leukodystrophy simulating chronic progressive multiple sclerosis. N Engl J Med 311(15):948–953. https://doi.org/10.1056/NEJM198410113111504
Schwankhaus JD, Katz DA, Eldridge R, Schlesinger S, Mcfarland H (1994) Clinical and pathological features of an autosomal dominant, adult-onset leukodystrophy simulating chronic progressive multiple sclerosis. Arch Neurol 51(8):757–766. https://doi.org/10.1001/ARCHNEUR.1994.00540200033013
Gao Yd, Ding M, Dong X, Jj Zhang, Azkur AK, Azkur D, Gan H et al (2021) Risk factors for severe and critically Ill COVID-19 patients: a review. Allergy 76(2):428–55. https://doi.org/10.1111/ALL.14657
Guaraldi G, Meschiari M, Cozzi-Lepri A, Milic J, Tonelli R, Menozzi M, Franceschini E et al (2020) Tocilizumab in patients with severe COVID-19: a retrospective cohort study. Lancet Rheumatol 2(8):e474. https://doi.org/10.1016/S2665-9913(20)30173-9
Mortezaee K, Majidpoor J (2022) Checkpoint inhibitor/interleukin-based combination therapy of cancer. Cancer Med 11(15):2934. https://doi.org/10.1002/CAM4.4659
Funding
Open access funding provided by Università degli Studi di Palermo within the CRUI-CARE Agreement.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
None.
Ethical approval and Informed consent
A written informed consent was signed by the patient for the standard diagnostic procedures and therapy. This consent included also the permit to use anonymized data for research purpose. A specific approval was also obtained by the local ethical committee.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Schirò, G., Iacono, S., Andolina, M. et al. Tocilizumab treatment in MOGAD: a case report and literature review. Neurol Sci 45, 1429–1436 (2024). https://doi.org/10.1007/s10072-023-07189-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10072-023-07189-7