Beruflich Dokumente
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Journal of Neuroimmunology
a r t i c l e i n f o a b s t r a c t
Article history: To clarify the efficacy of thymectomy among myasthenia gravis (MG) patients with and without thymoma. We
Received 25 October 2016 classified MG patients who underwent thymectomy into 3 groups, such as thymic atrophy group, thymic follic-
Received in revised form 22 December 2016 ular hyperplasia (TFH) group and thymoma group. We compared the data of clinical features and postoperative
Accepted 11 January 2017
prognosis at very short-term, short-term, and medium-term. The clinical course of MG patients with atrophic
Available online xxxx
thymus after thymectomy was even better than those of TFH or thymoma, in this retrospective study. However,
Keywords:
we found no significant differences in the comparison of mean dose of prednisolone between the 3 groups at each
Myasthenia gravis time point.
Thymus pathology © 2017 Published by Elsevier B.V.
Thymectomy
Anti-acetylcholine receptor antibody
Prednisolone
http://dx.doi.org/10.1016/j.jneuroim.2017.01.005
0165-5728/© 2017 Published by Elsevier B.V.
Please cite this article as: Nakahara, K., et al., Effect of thymectomy for thymic atrophy in myasthenia gravis: A retrospective study on 93 patients, J.
Neuroimmunol. (2017), http://dx.doi.org/10.1016/j.jneuroim.2017.01.005
2 K. Nakahara et al. / Journal of Neuroimmunology xxx (2017) xxx–xxx
classification (Jaretzki et al., 2000); and AChRAb status. MGFA classifica- Table 1
tion was based on Chest CT scans were performed for diagnosis of MG to Clinical features of patients with MG at pre-thymectomy and operative procedure.
screen for thymomas. The degree of TFH of the thymus was classified Thymic
into 5 grades according to the classification of the MG study group of Thymic follicular
the Ministry of Health and Welfare of Japan in 1977: grade 0, involuted atrophy hyperplasia Thymoma
group group group p-Value
thymus; grade I, accumulation of lymphocytes in the distended medul-
la; grade II, 1 follicle in 1 section; grade III, 2 to 4 follicles in 1 section; Number of patients 25 29 39
Age (yr) 64.1 43.8 ± 18.0 59.9 b0.001
and grade IV, N 5 follicles in 1 section or N1 follicle in each lobule. We de-
± 13.6 ± 12.3
fined grade 0 or grade I as thymic atrophy, and grade II or above as TFH Age at onset (yr) 59.5 37.8 ± 17.2 54.6 b0.001
in non-thymomatous MG. Treatment-related information included: ± 13.4 ± 12.6
MGFA post-intervention (PI) status (Jaretzki et al., 2000); age at thy- Late onset MG (%) 20 (80) 6 (21) 29 (76) b0.001
mectomy; thymic histology; current prednisolone (PSL) dose; course Age at thymectomy (yr) 60.8 39.1 ± 17.0 55.3 b0.001
± 12.7 ± 12.3
of PSL dose; use of calcineurin inhibitors (CNIs); use of pyridostigmine; Sex, female (%) 14 (56) 24 (83) 28 (72) 0.163
steroid pulse therapy; plasmapheresis (PP); and intravenous immuno- MGFA I (%) 0 (0) 2 (7) 7 (18) 0.339
globulin (IVIg). Histological analyses of the thymus were performed classification II (%) 24 (96) 23 (80) 26 (67)
after thymectomy. In the present study, diagnoses of thymic atrophy, III (%) 0 (0) 3 (10) 3 (8)
IV (%) 0 (0) 0 (0) 0 (0)
TFH and thymoma were made by pathologists, certified by the Japanese
V (%) 1 (4) 1 (3) 1 (2)
Society of Pathology, in our institute (Kondo and Monden, 2005). Unclassified 0 (0) 0 (0) 2 (5)
We classified the MG patients who underwent thymectomy into 3 (%)
groups, such as thymic atrophy group, TFH group and thymoma Anti-AChR Ab (nmol/L) 27.9 354.3 ± 1084.6 51.2 0.015
group, based on pathological findings. We compared the data of clinical ± 28.7 ± 69.4
PSL (mg) 1.2 ± 6.0 3.7 ± 9.6 5.1 0.198
features and thymectomy outcomes among pre-thymectomy, 1 month,
± 11.7
1 year, and 3 years after thymectomy. Tacrolimus (mg) 0.0 ± 0.0 0.0 ± 0.0 0.1 ± 0.5 0.494
Cyclosporin A (mg) 0.0 ± 0.0 0.0 ± 0.0 0.0 ± 0.0 1.000
2.2. Statistics VATS for thymectomy (%) 16 (64) 18 (62) 10 (26) 0.002
Please cite this article as: Nakahara, K., et al., Effect of thymectomy for thymic atrophy in myasthenia gravis: A retrospective study on 93 patients, J.
Neuroimmunol. (2017), http://dx.doi.org/10.1016/j.jneuroim.2017.01.005
K. Nakahara et al. / Journal of Neuroimmunology xxx (2017) xxx–xxx 3
Table 2
Intervention for exacerbation of MG during entire course.
Thymic atrophy group Thymic follicular hyperplasia group Thymoma group p-Value
Number of patients 25 29 39
Intravenous methylprednisolone (%) 1 (4) 4 (14) 5 (13) 0.472
Intravenous immunoglobulin (%) 0 (0) 0 (0) 6 (15) 0.014
Plasmapheresis (%) 0 (0) 0 (0) 0 (0) 1.000
Fig. 1. Changes of MGFA PI status after thymectomy each group. Thymic atrophy group, thymic follicular hypertrophy (TFH) group, and thymoma group significantly improved over time
(p b 0.001, respectively). And, significant differences were found between the 3 groups at 1 year and 3 years (p = 0.002, and b0.001, respectively). The red end of the spectrum indicated
the combined percentage of improving (CSR, PR, and MM), white bar indicated the a substantial decrease in pretreatment clinical manifestations or a sustained substantial reduction in MG
medications (I), and the blue end of the spectrum indicated the combined percentage of worsening (U and W). (For interpretation of the references to colour in this figure legend, the
reader is referred to the web version of this article.)
thymectomy in the thymic atrophy group was consistent with the re- pure effect of thymectomy in the present study. A prospective, multi-
sults. The clinical outcome of the thymic atrophy group was even better center, and clinical observation is necessary to confirm the relationships
than that of the TFH or thymoma group. between the severities of MG symptoms (e.g. quantitative MG score),
Recent studies also reported MG patients with thymic atrophy that antibody levels, thymic pathology, and the treatments (e.g. dose of PSL
showed similar clinical improvement as those with TFH (Ishii et al., and CNIs, the frequency of PP, IVIg, and steroid pulse therapy). In sum-
2007). The typical microscopic appearance in patients with non- mary, on the basis of our results we conclude that the clinical course of
thymomatous MG is TFH characterized by the prominent germinal cen- MG patients with atrophic thymus after thymectomy was even better
ters in the medulla. The germinal center is where B cells differentiate than that of patients with TFH or thymoma.
into the cells producing antibodies with high affinity to the antigens.
The biological roles of thymectomy in MG patients with TFH were de-
pendent upon removing the germinal center B cells in the thymus
(Okumura et al., 2003). The results in this study also showed that
TFH-associated MG patients improved with marked reduction of the ti-
ters of AChRAb (Okumura et al., 2003; Nikolic et al., 2013). The patho-
physiology of MG with hyperplastic thymus is becoming clearer. The
intrathymic antibody production, increased number of activated den-
dritic cells, and enhanced production of autoreactive T cells can explain
why thymectomy has a therapeutic effect in early onset MG. The etiolo-
gy of MG associated with thymoma is likely different from that of MG
associated with TFH. Abnormal positive selection of naïve T cells is an
essential pathological mechanism of the thymoma-associated MG.
However, the roles of thymic atrophy in the mechanism of MG remain
to be clarified (Flores et al., 1999). In the recent report, the expressions
of B cell activation markers in thymic microenvironments elevated his-
tologically in the atrophic thymus tissue of MG patients, similar to its
distribution in hyperplastic thymuses of MG patients (Chen et al.,
2011). There is the possibility that immune abnormalities can play piv-
Fig. 2. The changes of mean serum AChRAb titer before and after thymectomy in each
otal roles in the progression of MG patients with thymic atrophy. group. Mean serum AChRAb titers at 1 month after thymectomy: Thymic atrophy group
The important limitations of the present study were the retrospec- (30.0 ± 45.0); TFH group (283.4 ± 971.2); thymoma group (55.2 ± 87.5). Mean serum
tive design and the small number of subjects. Additionally, therapeutic AChRAb titers at 1 year after thymectomy: Thymic atrophy group (18.9 ± 21.9); TFH
intervention was actually different in the 3 groups, and additional group (214.8 ± 784.9); thymoma group (18.3 ± 21.5). Mean serum AChRAb titers at
3 years after thymectomy: Thymic atrophy group (7.9 ± 16.5); TFH group (34.6 ±
immunomodulation therapy after thymectomy depended on the at- 52.1); thymoma group (17.8 ± 32.7). In TFH group, mean serum AChRAb titer was
tending physician. The clinical course of each group may not have significantly high, and it decreased significantly at the time points after thymectomy,
reflected the effect of only thymectomy and may have obfuscated the compared to the other two groups (p = 0.015, 0.022, 0.053, and 0.123, respectively).
Please cite this article as: Nakahara, K., et al., Effect of thymectomy for thymic atrophy in myasthenia gravis: A retrospective study on 93 patients, J.
Neuroimmunol. (2017), http://dx.doi.org/10.1016/j.jneuroim.2017.01.005
4 K. Nakahara et al. / Journal of Neuroimmunology xxx (2017) xxx–xxx
MG myasthenia gravis;
MGFA MG foundation of America
MGFA PI status MGFA post-intervention status
PR pharmacologic remissions
PP plasmapheresis
PSL prednisolone
TFH thymic follicular hyperplasia
U unchanged
W worse
Acknowledgements
References
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I improved
IVIg intravenous immunoglobulin
MM minimal manifestation
Please cite this article as: Nakahara, K., et al., Effect of thymectomy for thymic atrophy in myasthenia gravis: A retrospective study on 93 patients, J.
Neuroimmunol. (2017), http://dx.doi.org/10.1016/j.jneuroim.2017.01.005