Autologous stem cell transplantation in a patient with refractory anti-MuSK-Positive myasthenia gravis and familial mediterranean fever

Berin Inan; Can Ebru Bekircan-Kurt; Haluk Demiroğlu; Hakan Göker; Sevim Erdem-Özdamar; Ersin Tan

doi:10.4103/nsn.nsn_197_21

LETTER TO EDITOR

Year : 2022 | Volume : 39 | Issue : 2 | Page : 115-118

Autologous stem cell transplantation in a patient with refractory anti-MuSK-Positive myasthenia gravis and familial mediterranean fever

Berin Inan¹, Can Ebru Bekircan-Kurt¹, Haluk Demiroğlu², Hakan Göker², Sevim Erdem-Özdamar¹, Ersin Tan¹
¹ Department of Neurology, Hacettepe University Faculty of Medicine, Ankara, Turkey
² Department of Internal Medicine, Division of Hematology, Hacettepe University Faculty of Medicine, Ankara, Turkey

Date of Submission	16-Oct-2021
Date of Decision	07-Feb-2022
Date of Acceptance	08-Feb-2022
Date of Web Publication	29-Jun-2022

Correspondence Address:
Berin Inan
Department of Neurology, Hacettepe University Faculty of Medicine, 06100, Ankara
Turkey

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/nsn.nsn_197_21

How to cite this article:
Inan B, Bekircan-Kurt CE, Demiroğlu H, Göker H, Erdem-Özdamar S, Tan E. Autologous stem cell transplantation in a patient with refractory anti-MuSK-Positive myasthenia gravis and familial mediterranean fever. Neurol Sci Neurophysiol 2022;39:115-8

How to cite this URL:
Inan B, Bekircan-Kurt CE, Demiroğlu H, Göker H, Erdem-Özdamar S, Tan E. Autologous stem cell transplantation in a patient with refractory anti-MuSK-Positive myasthenia gravis and familial mediterranean fever. Neurol Sci Neurophysiol [serial online] 2022 [cited 2023 Mar 28];39:115-8. Available from: http://www.nsnjournal.org/text.asp?2022/39/2/115/348902

Dear Editor,

Myasthenia gravis (MG) is an antibody-mediated autoimmune disease of the neuromuscular junction.^[1],[2] Acetylcholinesterase inhibitors are the initial therapy and the majority of patients need long-term immunosuppressive treatment.^[3],[2] Despite these treatment options, approximately 10% of patients with generalized MG, including those who are muscle-specific tyrosine kinase (MuSK)-positive, are treatment refractory.^[4],[5] Alternative immunotherapies such as rituximab can be considered for these patients.^[4],[6] Hematopoietic stem cell transplantation (HSCT) has also been used in the treatment of severe refractory MG.^[7],[8] However, experience is limited with only 11 reported cases.^{[4],[9],[10],[11],[12]} Herein, we report a patient with refractory MuSK-positive MG and familial Mediterranean fever (FMF) who was treated with HSCT and had a modest response.

A 26-year-old female presented with diplopia, ptosis, bilateral facial weakness, and dysphagia in June 2016. Her medical history revealed FMF, thalassemia minor, and colchicine-induced myopathy. She was on anakinra treatment for FMF. She was diagnosed as having MG through compatible neurologic examinations and single-fiber electromyography and hospitalized. She was negative for acetylcholine receptor (AchR) antibody but positive for MuSK antibody (1.79 nmol/L, reference range: <0.05, in an indirect immunofluorescence test). There was no thymic pathology in thorax computed tomography. Pyridostigmine (3 × 60 mg/day) and intravenous immunoglobulin (IVIG) (0.4 g/kg/day, 5 days) were started. However, pyridostigmine had to be discontinued due to severe fasciculations and cramps. Her myasthenic symptoms did not improve with IVIG, so seven sessions of plasmapheresis were performed. After seven sessions, her symptoms improved. Methylprednisolone (0.8 mg/kg/day) was also started but her myasthenic symptoms worsened and she developed myopathy (motor strength was 4/5 in proximal upper and lower extremities according to the Medical Research Council (MRC) Scale) after 2 weeks; therefore, the methylprednisolone had to be stopped.

Intermittent IVIG treatment was initially given twice a week, later, it was given once per week as maintenance treatment. She was discharged with significant clinical improvement. After 3 months, she was still on weekly IVIG treatment and was admitted to the hospital due to dysphagia after a respiratory infection. She was given IVIG in 5 consecutive days, resulting in clinical stabilization, and continued twice weekly. In January 2017, while on IVIG twice a week, she developed shortness of breath, bilateral ptosis, dysphagia, and proximal extremity weakness (4/5 according to the MRC Scale) and was admitted to the intensive care unit (ICU).

Noninvasive mechanical ventilation was administered. She underwent seven plasmapheresis sessions with clinical improvement. Azathioprine could not be given because of neutropenia (1100/μL, normal range: 1800–6400/μL) caused by anakinra treatment. We decided to continue with rituximab and intermittent plasmapheresis because she experienced two more myasthenic crises on IVIG. Until receiving approval for rituximab from local authorities, we inserted a permanent subclavian catheter for the maintenance of intermittent plasmapheresis (twice per week). Rituximab was started in March 2017, and she received 1000 mg/day twice with 15 days apart. Maintenance doses were planned at 6-month intervals. Unfortunately, a brachial artery-cephalic vein fistula had to be performed because of recurrent catheter infections and thrombosis. The frequency of myasthenic exacerbations did not change after rituximab (two courses) plus twice-weekly plasmapheresis. During these exacerbations, short-term methylprednisolone treatment was also begun. No significant improvement was observed.

The severity of myasthenic symptoms was between the MG Foundation of America classification Class IIIb and V; the treatment responses were not satisfactory. She was hospitalized six times, two of which were in the ICU, within 15 months after MG diagnosis. Thus, we decided to perform autologous HSCT (AHSCT).

Peripheral hematopoietic stem cells were mobilized using cyclophosphamide. Cyclophosphamide 4000 mg/m² was given after a day of hydration and filgrastim was begun at a dose of 48 mU on day 3 and continued until harvesting was completed. When the white blood cell count rose over 1000/dL, the CD34+ cell count was measured and when the number of cells was >20/mL, autologous hematopoietic stem cells were harvested through leukapheresis. Cyclophosphamide 12 mg/kg on days-6 through-3 and anti-thymocyte globulin 10 mg/kg on days-2 and-1 were given as a conditioning regimen. CD34+ cells (15.49 × 10⁶/kg) and 4.53 × 10⁸/kg mononuclear cells were infused at day 0 (November 16, 2017). The infusion was completed without complications. The absolute neutrophil count reached >500/μL on day 8, and the platelet count reached >50 × 10³/μL on day 10. Ten days after AHSCT, the patient developed a urinary tract infection treated with imipenem. On day 21, she was discharged.

Within 30 months after AHSCT, the patient was hospitalized three times because of neutropenic fever and myasthenic crisis. She needed four courses of rescue plasmapheresis. The patient remains on plasmapheresis twice weekly and rituximab treatment every 6 months. She also receives monthly IVIG infusions because of immunoglobulin deficiency that developed after AHSCT. The patient has been using anakinra on-demand for FMF due to neutropenia and immunoglobulin deficiency. The clinical course and maintenance treatments of the patient are presented in [Figure 1].

Figure 1: Clinical course and maintenance treatments of the patient. MPZ = Methylprednisolone, RTX = Rituximab, IVIg = Intravenous immunoglobulin, PExc = plasma exchange, MGFA = Myasthenia Gravis Foundation of America, ICU = intensive care unit, AHSCT = autologous hematopoietic stem cell transplantation. Colored arrows represent the continuation of the corresponding treatment

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In most cases, MG can be managed effectively with acetylcholinesterase inhibitors, corticosteroids, conventional immunosuppressants, and rapid immunomodulating therapies. Nevertheless, a subgroup of patients, including those with anti-MuSK-antibody-positive MG, remain treatment refractory.^[4],[13] Recently, rituximab has emerged as a preferred early therapy in anti-MuSK-antibody-positive MG based on accumulating observational data and clinical experience.^[13],[14] In our case, sex, age of onset, MuSK-antibody positivity, and FMF history were risk factors for a refractory disease course.^[4],[15] Moreover, she experienced adverse effects or complications with glucocorticoids, azathioprine, and intermittent plasmapheresis treatments. Rituximab was tried along with intermittent plasmapheresis sessions but it failed to prevent frequent exacerbations.

HSCT has been used in the treatment of various neurologic autoimmune diseases for the last two decades based on the assumption that reconstruction of the immune system eliminates autoimmunity.^[8] However, considerably few patients with MG have been treated with HSCT to date. We performed a search in PubMed by using “hematopoietic stem cell transplantation” and “myasthenia gravis” as keywords from 1986 to 2021 in the English language. We found 11 cases among 35 publications.^{[4],[9],[10],[11],[12]} The epidemiologic and clinical characteristics of the 11 cases are presented in [Table 1]. Eight (73%) patients^{[9],[11],[12]} were female. Eight patients were positive for AchR antibody,^{[4],[10],[11],[12]} one patient was positive for MuSK antibodies,^[9] and two patients were seronegative^[11] (MuSK antibody was not studied). All patients except one^[10] had undergone autologous HSCT. The mean age at HSCT was 43.5 years. Nine patients had complete remission, whereas two^[10],[12] had minor residual symptoms. After AHSCT, viral reactivation was reported in three patients and one patient developed a secondary autoimmune disease.^[11] One patient died 17 months after AHSCT because of recurrence and progression of concomitant lymphoma.^[11] No other serious adverse events were reported. Our patient was a 27-year-old woman with MuSK-positive MG and with concomitant autoinflammatory disease, FMF. Unfortunately, complete clinical and pharmacologic remission could not be achieved after AHSCT, but the frequency and severity of myasthenic exacerbations subsided and her quality of life improved.

Table 1: Characteristics of patients with myasthenia gravis who underwent hematopoietic stem cell transplantation in the literature

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Concomitant autoimmune diseases such as thyroiditis, systemic lupus erythematosus, and rheumatoid arthritis (RA) are present in approximately 15% of patients with MG and associated with poor prognosis.^[15],[16] Autoinflammatory and autoimmune diseases can also be seen together, as in our patient.^[17] A report of a 40-year-old woman with anti-AchR-positive MG, Morvan syndrome, and FMF described frequent relapses and only transient improvement in myasthenic symptoms despite corticosteroid, plasma exchange, and IVIG treatments. The authors speculated that FMF-related autoinflammation and increased pro-inflammatory cytokines contribute to the augmentation of myasthenic symptoms through the effect on Th17 and regulatory T cells.^[18] Similarly, we think that the presence of FMF may have increased the myasthenic exacerbations and complications of AHSCT in our case.

Anakinra is a recombinant human interleukin-1 (IL-1) receptor antagonist used in the treatment of FMF. It inhibits the binding of IL-1 to its receptor and prevents IL-1-mediated inflammation.^[19] In a study regarding the therapeutic effect of IL-1 receptor antagonists in an experimental autoimmune MG model, the authors suggested that inhibition of IL-1 might also limit the autoimmune response to AchR.^[20] On the other hand, in a study about the incidence of MG in patients with RA with and without treatment (including anakinra), the authors found that treatment did not influence the incidence of MG following an RA diagnosis.^[21] Our patient was leukopenia and had frequent infections. We used anakinra as on-demand due to these limitations, and we observed no protective effect of anakinra on myasthenic exacerbations.

In conclusion, despite limited experience, available data suggest that HSCT can be effective and may be the only therapeutic option in selected cases of severe, treatment-refractory MG. Further, research is warranted to evaluate the efficacy and safety profile of HSCT in MG more clearly.

Acknowledgment

The authors thank the staff of the neurology ward, neurology intensive care unit, and urology department for their efforts in the care of the patient.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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