CC BY
15
UDC 616.74+616.81]-009.17-07-08
O.I. Kalbus, N.P. Shastun, S.O. Makarov, Yu.V. Bukreyeva,
THE EVALUATION OF APPROACHES TO THE TREATMENT OF MYASTHENIA GRAVIS
https://doi.org/10.26641/2307-0404.2019.3.181886
O.V. Somilo
SE «Dnipropetrovsk medical academy of Health Ministry of Ukraine»
Department of Neurology and Ophthalmology
V. Vernadsky str., 9, Dnipro, 49044, Ukraine
ДЗ «Днтропетровська медична академiя МОЗ Украти»
кафедра неврологИ i офтальмологи
(зав. - д. мед.н., доц. О.В. Погорелое)
вул. Вернадського, 9, Днтро, 49044, Украша
e-mail: kalbus.dp@gmail.com
Цитування: Медичш перспективы. 2019. Т. 24, № 3. С. 80-86
Cited: Medicniperspektivi. 2019;24(3):80-86
Key words: myasthenia gravis, type of treatment, symptomatic treatment, basic treatment, immunomodulatory treatment, survival, treatment efficacy
Ключовi слова: мiастенiя, тип лшування, симптоматичне лшування, базове лшування, iмуномодулююче лiкування, виживанкть, ефективтсть л^вання
Ключевые слова: миастения, тип лечения, симптоматическое лечение, базовое лечение, иммуномодулирующее лечение, выживаемость, эффективность лечения
Abstract. The evaluation of approaches to the treatment of myasthenia gravis. Kalbus O.I., Shastun N.P., Makarov S.O., Bukreyeva Yu.V., Somilo O.V. Myasthenia gravis is a relatively rare autoimmune disease with an undetermined aetiology which affects neuromuscular junctions. Currently, the following approaches to the treatment of myasthenia gravis are mainly distinguished: symptomatic treatment with anticholinesterase inhibitors (AChEIs), immunomodulatory therapy ("basic" therapy) with glucocorticoids, cytostatics, monoclonal antibodies; surgical treatment — thymectomy; short-term treatment with plasmapheresis and intravenous administration of immunoglobulin. The efficiency of treatment approaches to myasthenia gravis in Ukraine remains insufficiently studied. The purpose of this work is to analyse the therapeutic approaches in patients with myasthenia gravis depending on the clinical form and severity of the disease. Between 2014 and 2017, 182 patients with myasthenia gravis have been examined, out of which 147 (80.8%) were the patients with the generalized form of the disease and 35 (19.2%) — with its ocular form. The clinical neurological examination included the collection of complaints, an anamnesis of disease and life as well as a neurological examination. In all the patients, the level of antibodies to acetylcholine receptors (AchR) and to muscle-specific tyrosine kinase (MuSK) has been measured, in terms of quantity as well, using the enzyme-linked immunosorbent assay (ELISA), and the presence of antibodies to titin and SOX1 has also been detected by means of indirect immunofluorescence. Of the total sample, less than a third (28.0%) of the patients examined received basic therapy; among them, there were no patients with the ocular form and only 34.7% — with the generalized form (p<0.001). Basic therapy is found more often among the patients with class II myasthenia gravis (51.9%), with a statistically significant (p< 0.001) higher share of the patients receiving such a therapy than in classes III and IV (26.6% and 22.6% respectively). The structure of therapy in patients with classes III and IV has not shown any statistically significant difference (p=0.658), with symptomatic treatment being the predominant type of therapy. Undergoing basic therapy reduces the chances of a severe clinical course of myasthenia gravis (the QMG score of 17 and higher) — 0R=0.52 (95.0% CI 0.14-0.90), p=0.032; fatal cases of the disease — 0R=0.36 (95.0% CI 0.02-0.70), p=0.049. When basic therapy is used, the survival rate of the patients (Figure 2) is 42.0 years on average (95% CI 42.0-42.7) which is considerably higher (p=0.021) compared to that of the patients receiving symptomatic treatment only — 33.0 years (95% CI 30.9-36.7). Immunomodulatory therapy was prescribed for only 28% of the patients in the total sample, for none of the patients with the ocular form of myasthenia gravis, and for 34.7% of the patients with the generalized myasthenia gravis. The prescription of immunomodulatory therapy reduces relative risks of a severe clinical course of myasthenia gravis — 0R=0.52 (95.0% CI 0.14-0.90), p=0.032. The prescription of immunomodulatory therapy decreases the probability of a fatal outcome of the disease — 0R=0.36 (95.0% CI 0.02-0.70), p=0.049). With the use of immunomodulatory therapy, the patient survival rate rises considerably reaching an average of 42.0 years (95% CI 42.0-42.7), which is much higher compared to that in the group of the patients receiving symptomatic treatment only — 33.0years (95% CI 30.9-36.7), p=0.021.
МЕДИЧН1ПЕРСПЕКТИВИ / MEDICNIPERSPEKTIVI
Реферат. Оцшка лшувальних пiдходiв при MiacTeHiT. Кальбус О.1., Шастун Н.П., Макаров С.О., Букреева Ю.В., Сомiло О.В. Мiасmенiя - eidnocno pidKe автотунне захворювання з невизначеною eтiологieю, що характеризуется ураженням нервово-м'язових синапов. На цей час видшяють так основнi напрямки лiкування мiастeнii: симптоматичне л^вання - антихолiнeстepазнi препарати (АХЕП); iмуномодулюючe л^вання («базове» л^вання) - глюкокортико1ди, цитостатики, моноклональт антитша; хipуpгiчнe л^вання - тимeктомiя; короткострокове л^вання - плазмаферез, iмуноглобулiн внутршньовенно. Оцiнка eфeктивностi л^вальних пiдходiв при мiастeнii в Укра'ш до цього часу залишаеться недостатньою. Метою цei роботи був анализ лжувальних пiдходiв у хворих на мiастeнiю залежно вiд кл^чно' форми та тяжкостi захворювання. З 2014 по 2017 рж було обстежено 182 хворих на мiастeнiю, з них 147 (80,8%) пацieнтiв з генералгзованою формою захворювання, 35 (19,2%) - з очною. Клiнiко-нeвpологiчнe обстеження включало збip скарг, анамнезу захворювання та життя, нeвpологiчнe обстеження. Уам хворим визначали piвeнь антитш до peцeптоpiв ацeтилхолiну (AchR) та м 'язово-спeцифiчноi тирозин-ктази (MuSK) методом iмунофepмeнтного анал1зу (ELISA), в т.ч.кшьюсно, а також визначали наявнкть антитш до титину та SOX1 методом непрямо'1' iмунофлюоpeсцeнцii. 1з загально'1' вибipки менше третини (28,0%) обстежених пацieнтiв приймали базове л^вання, серед них жоден пацieнт з очною формою захворювання та лише 34,7% - з генералгзованою (р<0,001). Базове л^вання бшьшою мipою було представлене серед хворих з II класом мiастeнii (51,9%), що статистично значуще перевищувало (р<0,001) частку таких хворих у III та IV класах (26,6% та 22,6% вiдповiдно). Структура л^вання у хворих III-го та IV-го клаав статистично значуще не вiдpiзнялася (р=0,658) i переважаючим типом л^вання була симптоматична тератя. Прийом базово'1' терапН знижуe шанси тяжкого перебшу мiастeнii (QMG вiд 17 балiв та вище) - ВШ=0,52 (95,0% ДI 0,14-0,90), р=0,032; летальних випадюв захворювання - ВШ=0,36 (95,0% ДI 0,02-0,70), р=0,049. При викоpистаннi базово'1' терапи виживатсть пацieнтiв становить у середньому 42,0 роки (95% ДI 42,0-42,7), що суттeво вище (p=0,021) поpiвняно з пацieнтами з використанням виключно симптоматичного л^вання - 33,0роки (95% ДI 30,9-36,7). Ыуномодулююче л^вання було призначено лише 28% хворих iз загальноi вибipки, жодному пацieнту з очною фомою мiастeнii та 34,7% хворих з генералгзованою мiастeнieю. Призначення iмуномодулюючого л^вання знижуe вiдноснi шанси тяжкого переб^ мiастeнii (ВШ=0,52 (95,0% ДI 0,14-0,90), р=0,032. Призначення iмуномодулюючого л^вання знижуe шанси летальних випадюв захворювання (ВШ=0,36 (95,0% ДI 0,02-0,70), р=0,049). При викоpистаннi iмуномодулюючоi терапи виживатсть пацieнтiв значно пiдвищуeться та становить у середньому 42,0 роки (95% ДI 42,0-42,7), що суттeво вище поpiвняно з групою пацieнтiв, як отримували виключно симптоматичне л^вання - 33,0роки (95% ДI 30,9-36,7), p=0,021.
Myasthenia gravis is a relatively infrequent autoimmune disease, which nevertheless leads to significant economic costs and social losses. It is associated with the production of autoantibodies to acetylcholine receptors (AchR) or to muscle-specific tyrosine kinase (MuSK). Particular role in its development is attributed to titin antibodies. Myasthenia gravis affects post-synaptic terminal of neuro-muscular junctions, however the aetiology of this disease is still undetermined [1-4, 10].
Initially, myasthenia gravis presents with fatigue and extraocular muscle weakness at early stages, but at a later stage it advances into the generalized form, while these symptoms progress to pathological fatigue and weakness of limb and/or bulbar muscles [3, 10].
The incidence and prevalence of myasthenia gravis is higher in more economically developed countries. Accordingly, in the United States the incidence of myasthenia gravis reaches 200 cases per 1 million population a year, whereas it varies between other countries and populations, ranging from 17 to 104 cases per 1 million people a year. Despite significant advancements in diagnostics, treatment approaches, and improved overall prognosis of the disease since the beginning of the millennia, the occurrence of the disease has grown largely among the elderly (over 60 years of age) [5-9].
The classification of myasthenia proposed by MGFA (Myasthenia Gravis Foundation of America) is used in most countries around the world. It states that the disease can be divided into 5 classes: class
1 - ocular form; classes II-IV - generalized form: mild, moderate, and severe respectively; class V -generalized, with patients classified under this category that require intubation and/or mechanical ventilation. Each of the classes II-IV is divided into
2 subclasses: A - with predominant weakness and pathological fatigue of limb muscles; B - with predominant weakness and pathological fatigue of bulbar and/or orofacial muscles. Notwithstanding the ease of use and accessibility of this classification, it does not, however, at all times takes into account the individual manifestations of certain symptoms of each particular patient [3, 10, 11].
Currently, the proposed treatment methods of myasthenia gravis are as follows: symptomatic treatment with anticholinesterase inhibitors (AChEIs), immunotherapy ("basic" therapy) with glucocorti-coids, cytostatics, monoclonal antibodies; thymec-tomy (mostly effective in the first 2 years following the onset of primary symptoms); short-term treatment with plasmapheresis and/or intravenous immu-noglobulin (in myasthenic crises cases or worsening of symptoms) [4, 10].
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The primary goal of therapy is twofold: to achieve complete stable remission (without the use of pharmacological treatment) or to reach pharmacological remission (a patient does not need to take AChEIs). To accomplish sustained pharmacological remission, in most cases, a combination of therapeutic treatments is used. For example, immuno-therapy together with symptomatic treatment is generally recommended [3, 10].
Nonetheless, decompensation and development of complications are commonly seen in the treated myasthenia gravis patients in Ukraine. This can be attributed to the fact that the preferred treatment in many instances is symptomatic only, which makes sustained stabilization of the patient's condition impossible.
The efficiency of treatment approaches to myas-thenia gravis in Ukraine remains insufficiently studied.
The purpose of this work is to analyse the therapeutic approaches in patients with myasthenia gravis depending on the clinical form and severity of the disease.
MATERIALS AND METHODS OF RESEARCH
Between 2014 and 2017, 182 patients with mya-sthenia gravis were included into the study, out of which 147 (80.8%) were the patients with the generalized form of the disease and 35 (19.2%) - with its ocular form.
The clinical neurological examination included the collection of complaints, an anamnesis of disease and life as well as a neurological examination. Besides, the first symptoms of the disease, the period between the first symptoms and the diagnosis has been evaluated. To determine the clinical form of myasthenia gravis, the MGFA classification has been applied. For the quantitative assessment of myasthenia gravis manifestations, the QMG scale (Qualitative Myasthenia Gravis Scale) has been used. The type of therapy for each individual patient has been evaluated separately by carrying out a statistical analysis of the following types of therapy: symptomatic (with AChEIs), basic (options of a combination of prednisolone and/or cytostatics with/without AChEIs), and the absence of therapy.
In all the patients, the level of antibodies to acetylcholine receptors (AchR) and to muscle-specific tyrosine kinase (MuSK) has been measured, using the enzyme-linked immunosorbent assay (ELISA), and the presence of antibodies to titin and SOX1 has also been detected by means of indirect immunofluorescence. The above-mentioned tests were carried out using the facilities of the clinical diagnostic laboratory of the "Dnipropetrovsk Regio-
nal Clinical Hospital named after I.I. Mechnikov" Municipal Institution.
During mathematical processing, the nonpara-metric statistical methods have been used due to the deviation of quantitative data values from a normal distribution (the Shapiro-Wilk test). The mean values are represented as a median (Mdn) and an interquartile range (25%; 75%). Computer-aided statistical processing of the research results has been performed by means of the following software products: Microsoft Excel (Microsoft Office 2016 Professional Plus, Open License 67528927) and STATISTICA 6.1 (StatSoftInc., serial No. AGAR909E415822FA). When testing statistical hypotheses, the threshold value for the significance level has been set at p<0.05.
The research participants were recruited into the study on the basis of their informed consent in accordance with international standards of medical ethics.
RESULTS AND DISCUSSION
Among the examined patients, women prevailed - 128 (70.3%), the number of men was 54 (29.7%); the female to male ratio was 2.37:1. Among the patients with the generalized form of the disease, there was a statistically significant larger proportion of males compared to those with the ocular form (p =0.027). However, no statistically significant differences between the disease classes and subclasses (p>0.05) in the total sample breakdown by gender have been found (Tab. 1).
At the time of the survey, all the patients ranged in age from 18 to 83 years. The median age of the examined patients was 52.0 years with an interquartile range (34.0; 65.0). The data on the age distribution by the disease forms, classes, and subclasses of myasthenia gravis within the groups and in total could not be modelled using the normal (Gaussian) distribution (p<0.05 according to the Shapiro-Wilks criterion).
The segmentation of the patients by gender, age, and results of the immunological examination is shown in Table 1.
In terms of the structure of therapeutic treatment which included, as mentioned above, symptomatic treatment (AChEIs in isolation), basic therapy (options of a combination of prednisolone and/or cyto-statics with/without AChEIs), and the absence of therapy, the difference between the patients with one or another form of myasthenia gravis was statistically significant (p<0.001) (Fig. 1).
Of the total sample, less than a third (28.0%) of the patients examined received basic therapy; among them, there were no patients with the ocular form and only 34.7% - with the generalized form (p<0.001).
Table 1
Distribution of the patients by gender, immunologic type, and myasthenia gravis class (according to MGFA)
Characteristics
Total sample Ocular form Class I Generalized form
Total II—A II-B Class II III-A III-B Class III IV-A IV-B Class IV
Total number, 182 35 147 37 15 52 35 29 64 14 17 31
n (%) (100) (19.2) (80.8) (20.3) (8.2) (28.6) (19.2) (15.9) (35.2) (7.7) (9.3) (17.0)
Gender, n (%)
Females
Males
128 30 98 26 10 36 22 19 41 9 12 21 p1=0.027
(70.3) (85.7) (66.7) (70.3) (66.7) (69.2) (62.9) (65.5) (64.1) (64.3) (70.6) (67.7) p2=0.151
P3=0.473
54 5 49 11 5 16 13 10 23 5 5 10
(29.7) (14.3) (33.3) (29.7) (33.3) (30.8) (37.1) (34.5) (35.9) (35.7) (29.4) (32.3)
Detected antibodies, n (%)
AchR-AB
MuSK-AB
TITIN-AB
SOX1-AB
124 (68.1)
16 (8.8)
53 (29.1)
10 (5.5)
16 (45.7)
0
(0)
0
(0)
0
(0)
108
(73.5)
16 (10.9)
53 (36.1)
10 (6.8)
27 (73.0)
2 (5.4)
17
(46.0)
2 (5.4)
8
(53.3)
4
(26.7)
5
(33.3)
0
(0)
35 (67.3)
6
(11.5)
22 (42.3)
2 (3.9)
27 (77.1)
0 (0)
10 (28.6)
1
(2.9)
20
(69.0)
7
(24.1)
10 (34.5)
5
(17.2)
47 (73.4)
7
(10.9)
20 (31.3)
6 (9.4)
13 (92.9)
0 (0)
7
(50.0) 1
(7.1)
13 (76.5)
3
(17.7)
4
(23.5) 1
(5.9)
26 (83.9)
3 (9.7)
11
(35.5)
2 (6.5)
P1=0.002 P2=0.006 P3=0.015
P1=0.087 P2=0.235 P3<0.001
P1<0.001 P2=0.002 P3=0.001
P1=0.240 P2=0.239 P3=0.084
The average level of antibody titer among the patients in whom the relevant antibodies have been detected, Mdn (25%, 75%)
AchR-AB 4.05 0.8 4.8 1.8 2.2 1.8 4.8 5.55 5.4 7.1 9.7 7.6 P1<0.001
(1.55; (0.6; (2.4; (0.9; (1.05; (0.9; (3.5; (4.45; (3.9; (5.4; (6.9; (6.1; P2<0.001
6.55) 1.2) 7.05) 2.4) 3.3) 2.5) 8.1) 6.5) 6.6) 9.1) 10.2) 9.8) P3<0.001
MuSK-AB 6.0 - 6.0 1.45 1.05 1.25 - 6.2 6.2 - 10.8 10.8 -
(1.45; (1.45; (1.3; (0.85; (0.9; (5.9; (5.9; (9.9; (9.9; -
6.95) 6.95) 1.6) 1.65) 1.6) 6.7) 6.7) 11.2) 11.2) P3<0.001
Notes: * - differences between the groups according to the x2 criterion, including the Yates's correction for the index values closest to 0: p1 -between the forms of myasthenia gravis; p2 - between the classes of myasthenia gravis; p3 - between class I of myasthenia gravis and subclasses of classes II-IV of the generalized form of myasthenia gravis.
After analysing the distribution of the type of therapy by the form of myasthenia gravis, the following data have been obtained. Basic therapy is found more often among the patients with class II myasthenia gravis (51.9%), with a statistically significant (p<0.001) higher share of the patients
receiving such a therapy than in classes III and IV (26.6% and 22.6% respectively). The structure of therapy in patients with classes III and IV has not shown any statistically significant difference (p=0.658), with symptomatic treatment being the predominant type of therapy (Tab. 2).
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□ No therapy □ Symptomatic treatment Q Basic therapy
Note. Differences between the groups — p<0.001 according to the x2 criterion
Fig. 1. Distribution of the examined patients with different forms of myasthenia gravis by the type of therapy (%)
From this, a mediated inference that the use of basic therapy leads to reduced manifestations of myasthenia gravis and lowering its class can be drawn. A smaller percentage of the patients with classes III and IV myasthenia gravis undergoing basic therapy indicates the inadequacy of prescribing this therapy for such patients based on clinical manifestations of the disease.
Overall, the findings suggest that the patients with generalized myasthenia gravis among the examined patients are not sufficiently covered by basic therapy, despite its relatively low cost and availability in Ukraine. This may be due to the lack of awareness among some neurologists of the modern principles of myasthenia gravis treatment.
Table 2
Distribution of the examined patients with myasthenia gravis by the type of therapy according to the disease class (%)
Therapy Class I n=35 Class II n=52 Class Ill n=64 Class IV n=31
n % n % n % n %
No therapy 12 34.3 12 23.1 14 21.9 5 16.1
Symptomatic treatment 23 65.7 13 25.0 33 51.6 19 61.3
Basic therapy 0 0 27 51.9 17 26.6 7 22.6
Note: Differences between the classes — p<0.001 according to the x2 criterion
When making clinical comparisons, we come to a conclusion that the use of basic therapy is associated with the generalized form of the disease (the phi-coefficient 9=0.30), a higher class (9=0.40) and subclass (9=0.44) of myasthenia gravis.
As a result of the rank correlation analysis, reliable (p<0.05) correlations between the type of therapy (basic, symptomatic, no therapy) and a thymoma (Spearman's correlation coefficient p=0.20; p=0.006), thymectomy (p=0.22; p=0.002), the intensity of symptoms — the number of the first symptoms (p=-0.16; p=0.026), the presence (p=0.17; p=0.019) and the titer of antibodies to AchR (p=0.20; p=0.006), the presence (p=-0.15; p=0.039)
and the titer of antibodies to MuSK (p=-0.15; p=0.039), the presence of antibodies to titin (p=0.32; p<0.001) have been found.
Undergoing basic therapy reduces the chances of a severe clinical course of myasthenia gravis (the QMG score of 17 and higher) - OR=0.52 (95.0% CI 0.14-0.90), p=0.032; fatal cases of the disease -OR=0.36 (95.0% CI 0.02-0.70), p=0.049.
When basic therapy is used, the survival rate of the patients (Fig. 2) is 42.0 years on average (95% CI 42.0-42.7) which is considerably higher (p=0.021) compared to that of the patients receiving symptomatic treatment only - 33.0 years (95% CI 30.9-36.7).
1,04
1,02
1,00
0,98
0,96
0,94
Û 0,92
0,90
0,88
Finish. Censor.
3aBepm. + ^rsypiiip.
I I I I I I I I I I I I II-h
II I I I I I I I I
I III-H- Symptomatic treatment
_ Basic therapy
10 15 20 25 30 Tinte, years
35
40
45
50
0
5
Fig. 2. Cumulative survival rate of the patients with myasthenia gravis by the type of therapy using the Kaplan-Meier method
CONCLUSIONS
1. Immunomodulatory therapy was prescribed for only 28% of the patients in the total sample, for none of the patients with the ocular form of myasthenia gravis, and for 34.7% of the patients with the generalized myasthenia gravis.
2. The prescription of immunomodulatory therapy reduces relative risks of a severe clinical course of myasthenia gravis - 0R=0.52 (95.0% CI 0.140.90), p=0.032.
3. The prescription of immunomodulatory therapy decreases the probability of a fatal outcome of the disease - 0R=0.36 (95.0% CI 0.02-0.70), p=0.049).
4. With the use of immunomodulatory therapy, the patients survival rate rises considerably reaching an average of 42.0 years (95% CI 42.0-42.7), which is much higher compared to that in the group of the patients receiving symptomatic treatment only — 33.0 years (95% CI 30.9-36.7), p=0.021.
Conflict of interests.
The authors have no conflict of interests.
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Стаття надшшла до редакцп 03.07.2019
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