I ncl usi on body myosi t i s wi t h granul omaf ormat i on i n muscl e t i ssue
著者Sakai  Kenj i ,  I keda Yoshi hi sa,  I shi da Chi ho,Mat sumot o Yasuko,  Ono Kenj i ro,  I wasa Kazuo,Yamada Masahi t o
j ournal  orpubl i cat i on t i t l e
Neuromuscul ar Di sorders
vol ume25
number9
page range706- 712
year2015- 09- 01
URLht t p: //hdl . handl e. net /2297/43403
doi: 10.1016/j.nmd.2015.06.460
Sakai  1 
Inclusion body myositis with granuloma formation in muscle tissue 
Kenji Sakai a, Yoshihisa Ikeda a,b, Chiho Ishida a,b, Yasuko Matsumoto a,c, Kenjiro Ono 
a, Kazuo Iwasa a, Masahito Yamada a 
a Department of Neurology and Neurobiology of Aging, Kanazawa University 
Graduate School of Medical Sciences, Kanazawa, Japan 
b Department of Neurology, National Hospital Organization Iou Hospital, Kanazawa, 
Japan 
c Department of Neurology, Ishikawa Prefectural Central Hospital, Kanazawa, Japan   
Correspondence to: Dr Kenji Sakai 
Department of Neurology and Neurobiology of Ageing, Kanazawa University 
Graduate School of Medical Science 
13-1 Takara-machi, Kanazawa 920-8640, Japan 
Fax: +81-76-234-4253 
Phone: +81-76-265-2292 
E-mail: ksakai@med.kanazawa-u.ac.jp 
Sakai  2 
Conflicts of interest 
Author contributions 
Dr. Sakai: study concept and design, analysis and interpretation of data, statistical 
analysis, drafting/revising the manuscript.  Dr. Ikeda, Dr. Ishida, Dr. Mastumoto and 
Dr. Ono: clinical data collection, pathological examination of muscle tissues, and 
revising the manuscript.  Dr. Iwasa: collection and interpretation of data, pathological 
examination, drafting/revising the manuscript.  Dr. Yamada: drafting/revising the 
manuscript, study supervision. 
Funding source 
This work was not supported by any grant. 
Sakai  3 
Abstract 
Inclusion body myositis is a form of inflammatory myopathy.  We identified 4 cases of 
inclusion body myositis showing granuloma formation in muscle tissue and aimed to 
assess the features of this atypical form of the inclusion body myositis. 
We retrospectively reviewed consecutive patients who satisfied European 
Neuromuscular Centre IBM Research Diagnostic Criteria 2011.  Then, we assessed 
clinical profiles and pathological findings in patients with inclusion body myositis 
with granuloma and compared these findings with those of typical inclusion body 
myositis without granuloma.    
We identified 15 patients with inclusion body myositis.  Four patients 
showed granuloma formation in muscle tissue in addition to typical pathological 
features of inclusion body myositis.  Granulomas comprised a mixture of 
inflammatory cells, such as macrophages, epithelioid histiocytic cells, and 
lymphocytes.  One patient was found to have mediastinal granulomatous 
lymphadenopathy; however, the evidence in other patients was insufficient for a 
diagnosis of systemic sarcoidosis.  There were no significant differences between 
groups with and without granuloma regarding clinical manifestations, laboratory 
Sakai  4 
findings, response to immunomodulating therapies, or myopathological profiles.   
We established a new form of inclusion body myositis showing granuloma 
formation in muscle tissue.  Inclusion body myositis and granuloma formation could 
have identical pathomechanisms concerning dysregulation of autophagy.  
(198 words) 
Key words: inclusion body myositis; granuloma; rimmed vacuole; autophagy 
Sakai  5 
Abbreviations 
COX, cytochrome C oxidase; ENMC, the European Neuromuscular Centre; GM, 
granulomatous myositis; HE, hematoxylin and eosin; HLA, human leukocyte antigen; 
IBM, inclusion body myositis; IVIg, intravenous immunoglobulin; TLR, toll-like 
receptor  
1. Introduction 
Inclusion body myositis (IBM) is a type of inflammatory myopathy characterized by T 
lymphocyte infiltration around muscle fibers and the presence of rimmed vacuoles [1].  
In comparison to other types of inflammatory myopathy, including polymyositis and 
dermatomyositis, patients with IBM demonstrate an unfavorable response to 
immunosuppressive therapy [1].  The pathomechanisms of IBM remain uncertain.  
Inflammatory processes and degenerative mechanisms are both responsible for the 
development of this muscular disorder.   
 Granulomas are pathological structures comprising giant cells, 
macrophage-like epithelioid cells, and lymphocytes.  The most common condition 
associated with non-caseating granuloma formation in muscle tissues is sarcoidosis 
Sakai  6 
followed by foreign-body reactions and infectious conditions; however, 
granulomatous myositis (GM) is a type of inflammatory myopathy containing 
granulomas without any evidence of systemic sarcoidosis despite intensive clinical 
investigations [2].   
 Although there are several reported cases that presented features of both 
IBM and sarcoidosis [3-5], the relationship between IBM and granuloma formation 
remains to be clarified.  In this study, we identified 4 patients with IBM showing 
granuloma formation in muscle tissues.  Somewhat surprisingly, granulomas were 
confined to skeletal muscle in 3 patients.  This study aimed to elucidate the features of 
IBM with granuloma by comparing these features with the clinical and 
histopathological features of patients with typical IBM.       
2. Materials and methods 
2.1 Patients 
We retrospectively reviewed consecutive patients who underwent an open muscle 
biopsy in our hospital and were referred to our department for pathological diagnosis 
of muscle biopsies between 2003 and 2013.  We selected IBM patients who satisfied 
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the European Neuromuscular Centre (ENMC) IBM Research Diagnostic Criteria 2011 
[6], and applied the classification as follows: clinicopathologically defined IBM, 
clinically defined IBM, and probable IBM.   
 Medical records were retrospectively reviewed for age at diagnosis, sex, 
sites of initial weakness, and duration from onset to diagnosis.  The following 
laboratory features determined at the time of diagnosis were obtained: the levels of 
serum creatine kinase, lactate dehydrogenase, aldolase, and myoglobin; levels of 
plasma C-reactive protein; and erythrocyte sedimentation rate.  In addition, we 
examined the presence of serum autoantibodies suggestive of other collagen disorders, 
hepatitis B antigens, and hepatitis C antibodies.   
 Special attention was paid to patients showing granulomas in muscle to 
exclude the possibility of systemic sarcoidosis.  A clinical diagnosis of sarcoidosis 
could be made on the basis of clinical, laboratory, and radiological features in addition 
to evidence of non-caseating granulomas in tissues.  Moreover, it is essential to 
exclude alternative diseases [7].  In terms of clinical presentation, pulmonary 
symptoms and abnormal chest radiographs including bilateral hilar lymphadenopathy 
are common; however, rarely patients may show only extrapulmonary manifestations 
Sakai  8 
[7.]  Granulomatous myositis is a type of myositis characterized by granuloma 
formation in muscle tissue, variable response to immunosuppressive therapies, and no 
evidence of systemic sarcoidosis [2].  Although it is uncertain whether GM is a limited 
form of systemic sarcoidosis, not all patients with GM develop symptoms of 
sarcoidosis [8].  To avoid making a diagnosis of sarcoidosis, the patients with IBM 
showing granuloma underwent intensive examinations, which included 
ophthalmological examinations, chest radiographs, and whole body examinations.  
Other disorders which might cause granulomatous myositis, such as tuberculosis 
infection, lymphoma, intestinal inflammatory disease, myasthenia gravis, 
foreign-body reaction, cryofibrinogenemia, and primary biliary cirrhosis [2], were 
excluded carefully by performing radiological and clinical investigations. 
 Most patients received immunosuppressive therapy as follows: 
corticosteroids (prednisone and methylpredonisolone), immunosuppressive drugs, and 
intravenous immunoglobulin (IVIg).  The results of these treatments were examined 
by retrospectively reviewing the medical records.  
 Written informed consent to participate in this study was obtained from the 
patients.  The study protocol was approved by the medical ethics committee of 
Sakai  9 
Kanazawa University. 
2.2 Pathological examinations 
Muscle biopsies were performed in all patients.  All samples were obtained by open 
biopsies and divided into several blocks.  Some specimens were immediately frozen in 
isopentane cooled with liquid nitrogen and stored at -80˚C until the experiments.  
Serial 6-µm-thick cryostat sections were cut and stained with hematoxylin and eosin 
(HE), modified Gomori trichrome, NADH-tetrazolium, Congo Red, and cytochrome 
C oxidase (COX).  The remaining samples were fixed with 10% buffered formalin.  
Pathological examinations were also performed on 5-µm-thick sections of paraffin 
embedded blocks using HE and Congo Red.  
 Selected formalin-fixed sections were immunostained with antibodies 
against phosphorylated neurofilaments (SMI-31; Covance, Emeryville, CA; 1:500), 
amyloid β protein (4G8; Covance; 1:5000), ubiquitin (Dako, Glöstrup, Denmark; 
1:8000), macrophages (CD68; Dako; 1:100), T lymphocytes (CD3; Dako; 1:20), B 
lymphocytes (CD20; Dako; 1:50), helper T lymphocytes (CD4; Dako; 1:400), and 
cytotoxic T lymphocytes (CD8; Dako; 1:20) using appropriate antigen retrieval 
Sakai  10 
methods.   Immunohistochemistry using antibodies against human leukocyte antigen-I 
(HLA-I; Dako; 1:200) and HLA-II (Dako, 1:100) was performed on frozen sections.  
The EnVision system (Dako) was used for these immunolabeling studies.  Peroxidase 
labeling was visualized with diaminobenzidine as the chromogen.    
Granulomas were defined as collections of inflammatory cells in which 
more than 60% of the inflammatory cells were macrophages or epithelioid histiocytic 
cells, as judged by HE or specific macrophage marker staining (CD68).  The presence 
of Langerhans-type or histiocytic giant cells was unnecessary to be judged as 
granulomas [9].  We paid special attention to exclude necrotic regions to avoid 
including caseating granulomas [9]. 
2.3 Case classification 
With reference to the pathological features of IBM (endomysial inflammatory 
infiltrates; rimmed vacuoles; protein accumulation; and upregulation of HLA class I 
around muscle fibers), we made a clinicopathological diagnosis of IBM [6].  Patients 
who demonstrated only these features were designated as typical IBM without 
granuloma group.  Patients showing granuloma formation in addition to typical IBM 
Sakai  11 
clinicopathologic characteristics were categorized into the IBM with granuloma 
group.  
2.4 Statistical analysis 
Differences in age at disease onset and in the results of laboratory tests between the 
typical IBM without granuloma group and the IBM with granuloma group were 
assessed using a Mann-Whitney U test.  Sex, diagnosis classification of IBM, initial 
weakness, and pathological findings were assessed using chi-square test and Fisher’s 
exact probability test.  Statistical significance was defined as p < 0.05.  Statistical 
analyses were performed using SPSS version 22 (IBM, Armonk, NY).   
3. Results 
3.1 Clinical profiles 
A total of 307 patients with myopathy were analyzed in our department during the 
study period.  Fifteen patients satisfied the clinical diagnostic criteria of IBM [6].  Five 
patients were categorized as clinicopathologically defined IBM.  Four and 6 patients 
were categorized as clinically defined IBM and probable IBM, respectively.  
Sakai  12 
Granuloma formation in muscle tissues was noted in 4 patients.  In these patients, one 
patient met the criteria for clinicopathologically defined IBM, whereas 2 and 1 
patients were categorized as clinically defined IBM and probable IBM, respectively.   
 Regarding IBM patients with granuloma, clinical features are summarized 
in Table 1.  One patient (patient 4) experienced dysphagia.  One patient (patient 3) 
showed lymphadenopathy with non-caseating granulomas in the mandibular region 
and mediastinum; however, clinical features suggesting sarcoidosis, such as bilateral 
hilar lymphadenopathy on chest radiography, erythema nodosum, uveitis, and 
maculopapular skin lesions, were absent.  Other patients had none of the above clinical 
or laboratory findings considered suggestive of sarcoidosis.  Several simultaneous 
diseases were observed in patients 2, 3 and 4 including hematological diseases and 
autoimmune disorders.  Patient 2 received a diagnosis of Sjögren syndrome and 
myelodysplastic syndrome.  Diagnosis of thyroiditis was given in patients 3 and 4.  
Patient 3 have also suffered from interstitial pneumonitis.  All patients received several 
immunomodulating treatments, including oral prednisone, methylpredonisolone pulse 
therapy, IVIg, and oral administration of tacrolimus.  No improvements were observed 
after the treatments.  
Sakai  13 
 A comparison of clinical manifestations and laboratory findings between the 
typical IBM without granuloma group and IBM with granuloma group are 
summarized in Table 2.  There were no significant differences regarding the clinical 
profile between these groups.  Several patients in the typical IBM without granuloma 
group were also positive for anti-nuclear antibody, anti-mitochondrial antibody, anti 
Ro/SS-A antibody, and exhibited a combined infection with hepatitis B virus and 
hepatitis C virus.  Although patients with typical IBM received immunomodulating 
treatments, such as oral prednisone, IVIg, and immunosuppressants, all patients 
showed progression of muscular weakness regardless of the treatments administered.  
Additionally, 2 patients were observed but were not treated apart from physical 
rehabilitation and exhibited slowly progressive muscular weakness.              
3.2 Pathological findings 
The quadriceps femoris muscle was the most frequently biopsied muscle in this series; 
however, 3 patients underwent a biopsy of the biceps brachii muscle.  The tibialis 
anterior muscle and semimembranous muscle were selected in 3 patients.   
All patients demonstrated pathological features typical of IBM, including 
Sakai  14 
many necrotic and regenerating fibers alongside CD8-positive T lymphocytes, 
mononuclear cell infiltration, a variable amount of rimmed vacuoles, positive HLA-I 
expression and protein accumulation in vacuoles (Figs 1A-C; Table 3).  Several cases 
demonstrated small amount of COX-deficient fibers.  In addition to theses typical 
structures as IBM, several granulomas were detected in the muscle tissues of the IBM 
with granuloma group (Figs 1A, D, E, 2A).  The granulomas comprised a mixture of 
inflammatory cells, such as epithelioid histiocytic cells surrounded by lymphocytes.  
These epithelioid cells showed macrophage-like features and were CD68 positive 
(Figs 2A-C).  No apparent multinucleated cells were observed in any patient.  Most of 
the lymphocytes around epithelioid cells were CD4-positive cells consistent with 
typical granulomas (Figs 2C-F) [10].  As regards the myopathological findings except 
for the presence of granuloma, there were no significant differences between the two 
groups (Table 3).   
4. Discussion 
We identified IBM with granuloma formation in the muscle tissues of 4 (27%) of 15 
consecutive patients who underwent muscle examinations.  All patients met current 
Sakai  15 
clinocopathological diagnostic criteria for IBM [6, 11].  Although mediastinal lymph 
node granulomas were histologically demonstrated in patient 3, other patients 
demonstrated granuloma formation confined to muscle tissues as determined by 
intensive examinations.  Hence, no patients received a diagnosis of sarcoidosis 
because of inadequate evidence. 
  Granulomas are structures associated with reaction to a foreign 
environment [2].  There are several reports of patients with GM showing the following 
features: myositis with granuloma, no evidence of sarcoidosis, and a good response to 
immunotherapy [2, 9].  Somewhat interestingly, some GM patients mimicked IBM in 
clinical characteristics; however, these cases showed no pathological features 
consistent with IBM, such as rimmed vacuole, amyloid deposition or abnormal protein 
accumulation in muscle fiber [12].  In a large muscle biopsy series, 12 cases (0.4%) of 
2985 specimens were identified as having granulomatous inflammation [8].  It is well 
known that some patients with sarcoidosis demonstrate asymptomatic granuloma 
formation in muscle; however, microscopic criteria for the differentiation of sarcoid 
lesions from other granulomatous myopathies are still lacking[10].  The relationship 
between GM and the limited lesions of sarcoidosis in muscle remains unknown.   
Sakai  16 
 It is uncertain whether granuloma formation in patients with the typical 
clinicopathologic characteristics of IBM is a coincidence or not.  There are several 
case reports showing a combination of sarcoidosis and IBM [3, 5].  Clinical 
manifestations related to sarcoidosis preceded IBM in all reported cases.  The authors 
of the above mentioned cases assumed that sarcoidosis was responsible for inducing 
IBM under uncertain circumstances [3, 5].  We presume that IBM and granuloma 
might share a similar pathogenesis on account of the following reasons.  Firstly, our 
cases of IBM with granuloma formation were indistinguishable from typical IBM in 
terms of the clinicopathologic profiles, including clinical manifestations, pathological 
findings, and an unfavorable response to therapy (Tables 2 and 3), suggesting that IBM 
with granuloma could be a form of IBM.  Secondly, inflammatory and degenerative 
mechanisms in IBM closely interrelate with each other [13].  A mouse model of IBM 
showing augmenting amyloid β protein in skeletal muscle demonstrated inclusion 
bodies and inflammatory infiltrates [14].  Abnormal protein accumulation in muscle 
fiber is a typical pathological feature of IBM patients.  Deposited proteins 
acknowledged as foreign bodies against immune systems might develop granuloma 
formation.  Finally, IBM and granuloma could share the same pathomechanistic 
Sakai  17 
background.  Sarcoidosis and IBM are Th1-mediated immune diseases [7, 15].  
Toll-like receptors (TLRs) are pattern-recognition receptors of the innate immune 
system that recognize conserved microbial motifs [16], and are involved in autophagy 
[17].  Mechanisms involving autophagy dysregulation are observed in IBM [18].  
TLRs are also associated with inflammation in idiopathic inflammatory myopathies 
including IBM [16, 18].  Toll-like receptor 2 (TLR2), a member of the TLR family, is 
associated with activation of granulomatous inflammation in sarcoidosis [19].  
Furthermore, autophagy-related genes may contribute to granuloma formation [20].   
 In conclusion, we established a new form of IBM showing granuloma 
formation.  Our results suggest that IBM with granuloma is identical to typical IBM in 
terms of the clinicopathological profile and an unfavorable response to 
immunomodulating therapies.  We presume that IBM and granuloma formation could 
share similar pathomechanisms in terms of autophagy dysregulation.  Further cases are 
necessary to clarify in detail the significance of granulomas in patients with IBM.  
 (2,074 words) 
Sakai  18 
Acknowledgements 
The authors thank Yumiko Kakuda and Yukari Yamaguchi for their excellent technical 
assistance.   
Sakai  19 
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15. De Paepe B, De Keyzer K, Martin J, et al. Alpha-chemokine receptors CXCR1–3 
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Figure captions 
Figure 1. Muscle biopsy findings in patients with inclusion body myositis (IBM) with 
granuloma.  Severe myopathic changes showing variations in fiber size, and 
infiltration of adipose tissue with granuloma formation (A).  Typical myopathologic 
features of IBM, including mononuclear cell infiltration in the endomysium with 
scattered rimmed vacuoles (B, C).  Granulomas comprising epithelioid cells 
surrounded by lymphocytes in the endomysium (D, E).  A from patient 1; B-D from 
patient 2; E from patient 4.  A, D, E hematoxylin and eosin stain; B, C modified 
Gomori-trichrome stain.  Bars 100 µm for A, 50 µm for B-E.      
Figure 2. Immunohistochemical profiles of the granuloma in patient 3.  Granuloma 
formation (A) was observed in muscle tissue comprising CD68-positive epithelioid 
cells (B), CD3- (C) and CD4-positive (D) T lymphocytes.  CD8-positive T 
lymphocytes were less numerous than CD4-positive cells (E).  Few CD20-positive B 
lymphocytes were identified (F).  A hematoxylin and eosin stain.  Bars = 100 µm.  
Sakai  23 
Table 1. Profiles of patients with inclusion body myositis with granuloma formation 
  Patient 1 Patient 2 Patient 3 Patient 4 
Age (onset; years) 51 59 56 67 
Sex Female Male Male Female 
Diagnosis classification  Clinically 
defined 
Probable Clinicopathologically  
defined 
Clinically 
defined 
Duration until diagnosis 
(months) 
72 30 192 28 
Granulomas in other 
organs 
None None Lymph nodes None 
Laboratory results     
CK (IU/L) 1765 385 1447 246 
LDH (IU/L) 575 294 582 244 
Aldolase (IU/L) 16 N.E. 22 6 
Myoglobin (ng/ml) N.E. 464.7 300 139.1 
CRP (mg/dl) 0 0.2 0.2 0 
ESR (mm; 1 hour) 16 25 12 31 
Other disorders None Sjögren 
syndrome, 
IP, thyroiditis Thyroiditis 
Therapy Corticosteroids Corticosteroids Corticosteroids,  Corticosteroids,  
IVIg, TAC TAC 
Response No No No No 
CK, creatine kinase; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; IP, 
Sakai  24 
interstitial pneumonitis; IVIg, intravenous immunoglobulin; LDH, lactate 
dehydrogenase ; MDS, myelodysplastic syndrome; N.E., not examined; TAC, 
tacrolimus 
Sakai  25 
Table 2. Clinical features of patients with inclusion body myositis (IBM) with and 
without granuloma formation 
Total Typical IBM 
without 
granuloma 
IBM with 
granuloma 
p value* 
  n = 15 n = 11 n = 4 
 Age at diagnosis (median 
years with range) 
62 (51–84) 70 (51–84) 58 (51–67) p = 0.169  
Male/female 9/6 7/4 2/2 p = 0.538 
Diagnosis classification of 
    Clinicopathologically 
defined  
5 4 1 p = 0.464 
Clinically defined  4 2 2  
Probable  6 5 1  
Initial weakness 
    Oral 0 0 0 p = 0.637 
Arm 3 2 1 
 Leg 12 9 3 
 Duration until diagnosis 
(median months with range) 
48 (12–192) 48 (12–84) 51 (28–192) p = 0.395 
Laboratory results  
(median with range) 
    CK (IU/L) 491 (186–1765) 491 (186–1469) 916 (246–1765) p = 0.601 
Sakai  26 
Total Typical IBM 
without 
granuloma 
IBM with 
granuloma 
p value* 
LDH (IU/L) 288 (166–582) 279 (166–370) 435 (244-582) p = 0.192 
Aldolase (IU/L) 10 (3–22) 9 (3–17) 16 (6–22) p = 0.309 
Myoglobin (ng/ml) 360 (67–563) 419 (67–563) 300 (139-465) p = 0.732 
CRP (mg/dl) 0.14 (0–0.6) 0.14 (0.01–0.6) 0.1 (0-0.2) p = 0.390 
ESR (mm/hour)  25 (12–64) 25 (13–64) 21 (12-31) p = 0.286 
IBM, inclusion body myositis; CK, creatine kinase; CRP, C-reactive protein; ESR, 
erythrocyte sedimentation rate; LDH, lactate dehydrogenase 
* p value was assessed between the typical IBM group and the IBM with granuloma 
group. 
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Table 3. Pathological features of the muscles of patients with inclusion body myositis 
(IBM) with and without granuloma formation 
Total Typical IBM 
without granuloma 
IBM with 
granuloma 
  n = 15 n = 11 n = 4 p value* 
Biopsied muscle Biceps brachialis 3 Biceps brachialis 2 Biceps brachialis 1  
 Quadriceps 8 Quadriceps 6 Quadriceps 2  
 Tibialis anterior 2 Tibialis anterior 2 Semimembranous 1  
 Semimembranous 1    
Inflammatory cell 
infiltration 
11/15 7/11 4/4 p = 0.242 
Rimmed vacuole 15/15 11/11 4/4 –† 
Congo 
Red-positive 
structures 
1/15 0/11 1/4 p = 0.267 
COX-deficient 
fibers 
5/15 4/11 1/4 p = 0.593 
Aβ-positive 
inclusions‡ 
6/13 4/10 2/3 p = 0.437 
Ubiquitin-positive 
inclusions‡ 
10/13 8/10 2/3 p = 0.580 
HLA-I positive 13/15 9/11 4/4 p = 0.524 
HLA-II positive 5/15 3/11 2/4 p = 0.459 
Aβ, amyloid β protein; COX, cytochrome C oxidase; HLA, human leukocyte antigen; 
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IBM, inclusion body myositis 
* p value was assessed between the typical IBM group and the IBM with granuloma 
group. 
† p value was not able to be calculated.  
‡ Paraffin-embedded sections were unavailable for one case in both groups.  