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ORIGINAL ARTICLE
Year : 2020  |  Volume : 23  |  Issue : 1  |  Page : 32-37
 

MuSK (Muscle Specific Kinase) positive myasthenia: Grave prognosis or undue prejudice?


Department of Neurology, All India Institute of Medical Sciences, New Delhi, India

Date of Web Publication21-Jan-2020

Correspondence Address:
Prof. Vinay Goyal
Room No: 706, Department of Neurology, All India Institute of Medical Sciences, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/aian.AIAN_302_19

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   Abstract 


Objectives: Patients with muscle-specific kinase (MuSK)-positive myasthenia are generally considered to have a grave prognosis. We present our experience of patients with myasthenia with different antibody status. This is followed by a short discourse on previous studies and the current view on MuSK-positive myasthenia, focusing on the associated prejudice. Materials and Methods: This study compares 23 patients with MuSK-positive myasthenia with 55 patients with acetylcholine receptor–positive myasthenia and 9 patients with double-seronegative myasthenia at a tertiary level center. Results: We did not find any significant difference in terms of clinical characteristics, treatment response to immunosuppressants, long-term prognosis, and quality of life. Conclusion: Seropositivity for antibodies should not be used in isolation to guide the management or predict the prognosis. Undue negative prognostication may affect the morale of patient. Clinical features and response to therapy in addition to antibody status must be considered before planning therapy.


Keywords: MuSK, myasthenia, prognosis, quality of life, rituximab


How to cite this article:
Samal P, Goyal V, Singh MB, Padma Srivastava M V. MuSK (Muscle Specific Kinase) positive myasthenia: Grave prognosis or undue prejudice?. Ann Indian Acad Neurol 2020;23:32-7

How to cite this URL:
Samal P, Goyal V, Singh MB, Padma Srivastava M V. MuSK (Muscle Specific Kinase) positive myasthenia: Grave prognosis or undue prejudice?. Ann Indian Acad Neurol [serial online] 2020 [cited 2020 Feb 24];23:32-7. Available from: http://www.annalsofian.org/text.asp?2020/23/1/32/268575





   Introduction Top


Since the first description of muscle-specific kinase (MuSK)-positive myasthenia (MuSK+ve MG) by Hoch et al. in 2001,[1] there have been multiple descriptions of clinical features of these patients. MuSK+ve MG are considered to have a more turbulent course at the beginning, and more severe symptoms at onset than acetylcholine receptor positive myasthenia (AChR+ve MG).[2] Neurologists tend to treat MuSK+ve MG more aggressively than AChR+ve MG. There has been much speculation about the utility of antibody status (acetylcholine receptor antibody positive (AChR+ve) vs MuSK antibody-positive) in prognostication and planning therapy.[3]


   Aim of the Study Top


This is a single-center, ambispective, comparative study comparing demographic and clinical characteristics, treatment response, and outcome of MuSK+ve MG with AChR+ve MG and patients with double-seronegative myasthenia (DN-MG).


   Materials and Methods Top


A retrospective chart review of MuSK+ve MG presenting to our institute from January 2010 to January 2016 was performed. All consecutive MuSK+ve MG who presented to our institute from February 2016 to July 2017 were also recruited. Demographic data, clinical details, and investigations were recorded. The diagnosis of myasthenia was made based on clinical, electrophysiological, and serological findings. All the antibody testing (anti-AChR or anti-MuSK) was done by radioimmune assay. The severity of disease and response to therapy were recorded according to Myasthenia Gravis Foundation of America (MGFA) recommendations. Response to treatment and outcome analysis were done only in those patients with adequate follow-up. Poor outcome was defined as one or more of the following: (1) postintervention status: unchanged, worse, exacerbation, death from MG; (2) inability to achieve low maintenance dose of pyridostigmine or steroids; (3) intravenous immunoglobulin (IVIg) or plasmapheresis (PLEX) on a regular basis. Quality-of-life assessment was done by MGQoL15r questionnaire. (4) Severe disease was defined as MGFA IV or MGFA V. Low maintenance treatment was defined as pyridostigmine ≤120 mg and prednisolone with a dose reduction by ≤50% from the maximum dose. Good response to acetylcholine-esterase inhibitors (AChEIs) was defined as more than 50% improvement.

Statistical analysis was done using STATA IC/11.1. Comparison of means/medians/proportions among three groups was done. The association between antibody type and patient outcome was analyzed by logistic regression. Significance was set at P ≤ 0.05.


   Results Top


In this study, 23 MuSK+ve MG, 55AChR+ve MG, and 9 DN patients were included [Table 1]. All the three groups were comparable to each other in terms of duration of illness and associated comorbidities. The proportion of females in MuSK+ve MG (69.6%) was significantly higher than that in AChR+ve MG (41.8%) (P = 0.02). There was no significant difference between the three groups in terms of age of onset, bulbar symptoms at onset, median interval between the first symptom and diagnosis, diurnal variation, positive neostigmine test, and positive repetitive nerve stimulation test. Thymic hyperplasia on contrast-enhanced computed tomography chest was significantly higher in AChR+ve MG (41.3%) than MuSK+ve MG (13.3%) (P = 0.04). The average number of myasthenic crisis per patient-year was not significantly different between the three groups (P = 0.99).
Table 1: Comparison of demographic, clinical characteristics, and investigations of patients with MuSK+ve MG with patients with AChR+ve MG and patients with double.seronegative MG

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None of the patients in any group had severe disease (MGFA IV or V) at onset. [Figure 1] shows the distribution of patients according to MGFA classification at disease onset, maximum severity of disease, and at the time of last follow-up. No significant difference between the three groups was observed.
Figure 1: Comparison of MGFA class at onset, maximum severity, and at last follow-up. Onset MGFA P = 0.59, max MGFA P = 0.63, last follow-up MGFA P = 0.91 AChR-MG: acetylcholine receptor–positive antibody myasthenia gravis; DN-MG: double-seronegative myasthenia gravis; MGFA: Myasthenia Gravis Foundation of America; MuSK-MG: muscle-specific kinase myasthenia gravis

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Good response to AChEI was similar in all groups. A significantly larger proportion of patients in MuSK+ve MG (84.2%) were prescribed both AChEI and steroids from the beginning compared with AChR+ve MG (37.2%) (P < 0.0005) [Table 2]. The maximum dose and incidence of adverse effects of AChEI or steroids were similar in three groups. Logistic regression analysis did not reveal any significant difference in incidence of adverse effects after adjusting for age, maximum dose, and duration of medication.
Table 2: Clinical comparison of treatment with AChEI and steroids between MuSK+ve MG group, AChR+ve MG group, and double-seronegative group

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Eighteen MuSK+ve MG, 40 AChR+ve MG, and 5 DN-MG patients were on azathioprine [Table 3]. There was no significant difference between them in terms of proportion of time on azathioprine compared with total duration of follow-up, maximum dose of azathioprine, incidence of adverse effects, or poor outcome.
Table 3: Clinical comparison of treatment with immunosuppressant drugs between MuSK+ve MG group, AChR+ve MG group, and double seronegative group

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Two MuSK+ve MG and six AChR+ve MG patients were given rituximab [Table 3]. Both MuSK+ve MG and five out of six AChR+ve MG had generalized MG. All but one patient (AChR+ve) had received multiple immunosuppressant drugs prior to initiation of rituximab.

Out of 32 patients who received 47 courses of IVIg (11 MuSK+ve MG, 19 AChR+ve MG, and 2 DN-MG) [Table 3], all the MuSK+ve MG and 15 out of 19 AChR+ve MG had good response to IVIg. Similarly, out of 28 patients who received 42 courses of PLEX (8 MuSK+ve MG, 20 AChR+ve MG) [Table 3], all the MuSK+ve MG and 15 out of 20 AChR+ve MG had good response to PLEX. There was no significant difference between the groups in terms of incidence of adverse effects.

A larger proportion of AChR+ve MG (43.1%) underwent thymectomy compared with MuSK+ve MG (16.7%) (P = 0.04). Out of the three MuSK+ve MG who underwent thymectomy, one had a thymoma and the other two were operated prior to 2000 (before routine testing of MuSK was started).

MuSK+ve MG had a nonsignificant increase in odds of developing severe disease [adjusted odds ratio (OR) 1.27, confidence interval (CI) 0.72–2.24, P = 0.41] or poor outcome (adjusted OR 1.93, CI 0.69–5.42, P = 0.70) after adjusting for age, sex, age of onset, duration of follow-up, and thymectomy compared with AChR+ve MG.

The MG-QOL15r score was compared between the three groups and there was no significant difference (P = 0.57) [Table 4].
Table 4: Comparison of outcomes between MuSK+ve MG group, AChR+ve MG group, and double-seronegative group

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   Discussion Top


This study did not find any significant difference between the three groups in terms of clinical symptoms and response to treatment. The long-term outcome (median duration of disease of 3.5–4.0 years) was also similar in all three groups. Interestingly, in previous studies also the long-term outcomes of MuSK+ve MG were similar to AChR+ve MG.[5],[6],[7],[8] In spite of this, the general notion among neurologists is that patients with MuSK+ve MG have grave prognosis.

Over the past two decades, much highlight has been placed on MuSK+ve MG with grave course of disease and patients with benign course of disease are seldom reported.[9] In our series, three patients never worsened beyond MGFA II. Gungor-Tuncer et al. analyzed the factors associated with benign course of disease in MuSK+ve MG (n = 46) and deduced that excellent response to corticosteroids in the first 3 months is a predictor for favorable outcome.[10]

In this study, a significantly larger proportion of patients with MuSK+ve MG (84.2%) were prescribed steroids from the beginning along with AChEI. This reflects the current trend in managing patients with MuSK more aggressively from initial treatment period, anticipating an aggressive course. Empirical initiation of steroids from the beginning leads to higher probability of adverse effects and the risk–benefit analysis of the same requires further evaluation. The treatment outcome between the groups was not significantly different, with equal proportion of patients achieving low maintenance dose of AChEI or steroids in each group. Also, the maximum dose of steroid and the proportion of time each patient was on steroids to the entire duration of follow-up in patients with MuSK+ve MG were similar to patients with AChR+ve MG.

No previous study has compared the response of conventional immunosuppression in MuSK+ve MG group with AChR+ve group. In this study (median duration of follow-up of 3.5–4.0 years), the response to treatment and adverse effects of azathioprine and mycophenolate mofetil (MMF) in MuSK+ve MG were similar to AChR+ve MG.

The current practice in most centers is to avoid thymectomy in non-thymoma MuSK-MG patients. In this study, apart from the single patient with MuSK-MG with thymoma and two other who were operated prior to 2000, none of the other patients with MuSK-MG underwent thymectomy.

A recent study by Tandan et al. analyzed the utility of rituximab in myasthenia and showed that MuSK+ve MG had a more robust response to rituximab compared with patients with AChR+ve MG.[11] Hehir et al. provided Class IV evidence in favor of rituximab in MuSK+ve MG.[12] It is noteworthy that in all these studies, the median severity prior to rituximab was MGFA IV and they had failed multiple immunosuppression therapies before rituximab was started. Díaz-Manera et al. recommended rituximab as an early therapeutic option after prednisolone.[3] Whereas we believe that the decision to start rituximab early in the disease is without definitive evidence, debatable, and may result in undue adverse effects.

In view of evidence of similar efficacy of azathioprine and MMF in MuSK+ve MG and AChR+ve MG in our study, MuSK+ve MG can initially be started on conventional immunosuppression and observed closely. The decision to give rituximab should be guided by the severity of symptoms and the course of disease rather than antibody status alone. The international consensus for management of myasthenia gravis also recommends that rituximab should be used in MuSK+ve MG who do not respond adequately to immunosuppression.[13]

None of the previous studies studied the quality of life of MuSK+ve MG. We found that the self-reported MG-QoL 15r score in MuSK+ve MG was similar to AChR+ve MG and double-seronegative patients.

MuSK+ve MG form a heterogeneous group and the course of disease may vary from patient to patient. While it is necessary to inform the patient about the expected course of disease and the necessity of regular follow-up, undue negative prognostication can affect the patient's morale, even those with benign course of disease.


   Conclusion Top


We compared the clinical features, response to therapy, and long-term prognosis of 23 MuSK+ve myasthenia with 55 AChR+ve MG and 9 DN-MG and did not find any significant difference between them. The study reinforces the fact that seropositivity for antibodies alone should not be used in isolation to guide the management or predict the prognosis of disease. Clinical features and initial response to therapy in addition to antibody status must be taken into account to plan therapy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Hoch W, McConville J, Helms S, Newsom-Davis J, Melms A, Vincent A. Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Nat Med 2001;7:365-8.  Back to cited text no. 1
    
2.
Guptill JT, Sanders DB. Update on muscle-specific tyrosine kinase antibody positive myasthenia gravis. Curr Opin Neurol 2010;23:530-5.  Back to cited text no. 2
    
3.
Díaz-Manera J, Martínez-Hernández E, Querol L, Klooster R, Rojas-García R, Suárez-Calvet X, et al. Long-lasting treatment effect of rituximab in MuSK myasthenia. Neurology 2012;78:189-93.  Back to cited text no. 3
    
4.
Burns TM, Sadjadi R, Utsugisawa K, Gwathmey KG, Joshi A, Jones S, et al. International clinimetric evaluation of the MG-QOL15, resulting in slight revision and subsequent validation of the MG-QOL15r. Muscle Nerve 2016;54:1015-22.  Back to cited text no. 4
    
5.
Lee JY, Sung JJ, Cho JY, Oh DH, Kim HJ, Park JH, et al. MuSK antibody-positive, seronegative myasthenia gravis in Korea. J Clin Neurosci Off J Neurosurg Soc Australas 2006;13:353-5.  Back to cited text no. 5
    
6.
Lavrnic D, Losen M, Vujic A, De Baets M, Hajdukovic LJ, Stojanovic V, et al. The features of myasthenia gravis with autoantibodies to MuSK. J Neurol Neurosurg Psychiatry 2005;76:1099-102.  Back to cited text no. 6
    
7.
Deymeer F, Gungor-Tuncer O, Yilmaz V, Parman Y, Serdaroglu P, Ozdemir C, et al. Clinical comparison of anti-MuSK- vs anti-AChR-positive and seronegative myasthenia gravis. Neurology 2007;68:609-11.  Back to cited text no. 7
    
8.
Guptill JT, Sanders DB, Evoli A. Anti-MuSK antibody myasthenia gravis: Clinical findings and response to treatment in two large cohorts. Muscle Nerve 2011;44:36-40.  Back to cited text no. 8
    
9.
Zouvelou V, Stamboulis E, Skriapa L, Tzartos SJ. MuSK-Ab positive myasthenia: Not always grave. J Neurol Sci 2013;331:150-1.  Back to cited text no. 9
    
10.
Gungor-Tuncer O, Yilmaz V, Toker A, Saruhan-Direskeneli G, Gulsen-Parman Y, Oflazer-Serdaroglu P, et al. Prompt response to prednisone predicts benign course in MuSK-MG. Eur Neurol 2017;78:137-42.  Back to cited text no. 10
    
11.
Tandan R, Hehir MK, Waheed W, Howard DB. Rituximab treatment of myasthenia gravis: A systematic review. Muscle Nerve 2017;56:185-96.  Back to cited text no. 11
    
12.
Hehir MK, Hobson-Webb LD, Benatar M, Barnett C, Silvestri NJ, Howard JF, et al. Rituximab as treatment for anti-MuSK myasthenia gravis: Multicenter blinded prospective review. Neurology 2017;89:1069-77.  Back to cited text no. 12
    
13.
Sanders DB, Wolfe GI, Benatar M, Evoli A, Gilhus NE, Illa I, et al. International consensus guidance for management of myasthenia gravis. Neurology 2016;87:419-25.  Back to cited text no. 13
    


    Figures

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