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Inclusion body myositis presenting as treatment-resistant polymyositis.

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INCLUSION BODY MYOSITIS PRESENTING AS
TREATMENT-RESISTANT POLYMYOSITIS
LEONARD H. CALABRESE, HIROSHI MITSUMOTO. and SAMUEL M. CHOU
Inclusion body myositis (IBM) has been viewed
as a distinct and rare form of inflammatory myopathy.
Previously reported findings from series of IBM patients
have suggested that clinical and pathologic features are
present which readily distinguish it from idiopathic
polymyositis. We report 4 cases of IBM presenting
clinically and pathologically as polymyositis, each of
which was refractory to therapy. Our data suggest that
IBM may be a more common and heterogeneous form of
inflammatory myopathy than has been previously suggested. Furthermore, IBM may be clinically and
electrophysiologically indistinguishable from polymyositis. Reasons for failing to recognize IBM by pathologic studies appear to include: the skip lesion nature of
the pathologic findings, failure to examine tissues by
electron microscopy, and a low level of suspicion or lack
of recognition. Because of its insidious clinical course
and its failure to respond to immunosuppressive therapy, IBM may be an important variant of treatmentresistant polymyositis.
In 1967, Chou described the presence of
intranuclear and cytoplasmic inclusions in 3 biopsy
specimens taken over an 18-month period from a
66-year-old man with polymyositis. Electron microscopic study of these inclusions revealed structures
that resembled paramyxovirus nucleocapsid, which is
suggestive of a possible pathogenic factor for chronic
polymyositis (1). Similar histopathologic findings were
reported subsequently by other investigators, and
gradually, clinical features were .identified which appeared to distinguish the disease known as inclusion
body myositis (IBM) (2-5). Based on reported patient
series, IBM in its fully developed form appears to have
histopathologic and clinical features that differentiate
it from idiopathic polymyositis or dermatomyositis.
We report 4 cases of IBM, each presenting as treatment-resistant polymyositis. We suggest that IBM
may be a more frequent cause of chronic inflammatory
myopathy than was previously recognized and that it
is a disorder capable of mimicking idiopathic
polymyositis for prolonged periods of time. Clinical
recognition of IBM is important since it is highly
resistant to treatment and appears to have a natural
history that is different from that of idiopathic
polymyositis.
~~
Presented at the 50th Annual Meeting of the American
Rheumatism Association, New Orleans, LA, June 1986.
From the Departments of Rheumatic and Immunologic
Disease, Neurology, and Pathology, Cleveland Clinic Foundation,
Cleveland, Ohio.
Leonard H. Calabrese, DO: Department of Rheumatic and
Immunologic Disease; Hiroshi Mitsumoto, MD: Department of
Neurology; Samuel M. Chou, MD: Department of Pathology.
Address reprint requests to Leonard H . Calabrese, DO,
FACP, Head, Section on Clinical Immunology, Department of
Rheumatic and Immunologic Disease, 9500 Euclid Avenue, Cleveland. OH 44106-4775.
Submitted for publication July 22, 1986; accepted in revised
form October 2, 1986.
Arthritis and Rheumatism, Vol. 30, No. 4 (April 1987)
PATIENTS AND METHODS
Each patient was referred to one of the authors
(LHC) for a second opinion regarding treatment-resistant
polymyositis. Charts for each patient were available for
retrospective review. All muscle biopsy specimens were
reviewed collectively by one author (SMC). Findings in
patient 1 have been reported elsewhere in detail (6). Using
the proposed diagnostic criteria presented in Table 1, each
patient was diagnosed as having definite, probable, or possible IBM. Clinical data from each of the patients are given
in Table 2.
398
CALABRESE ET AL
Table 1. Preliminary diagnostic criteria for inclusion body myositis (IBM)*
Pathologic criteria
Electron microscopy
1. Microtubular filaments in the inclusions (Figure 3)
Light microscopy
1. Lined vacuoles (Figure 2)
2. Intranuclear and/or intracytoplasmic inclusions (Figure 1)
Clinical criteria
1. Proximal muscle weakness (insidious onset)
2. Distal muscle weakness
3. Electromyographic evidence of a generalized myopathy (inflammatory myopathy)
4. Elevation of muscle enzyme levels (creatine phosphokinase and/or aldolase)
5. Failure of muscle weakness to improve on a high-dose corticosteroid regimen (at least 40-60
mglday for 3-4 months)
* Definite IBM = pathologic electron microscopy criterion 1 and clinical criterion 1 plus one other
clinical criterion. Probable IBM = pathologic light microscopy criterion 1 and clinical criterion 1 plus
3 other clinical criteria. Possible IBM = pathologic light microscopy criterion 2 plus any 3 clinical
criteria.
RESULTS
Muscular symptoms. The general distribution of
muscular weakness is described in Table 1. Only
patient 4 gave a history of muscular pain, as well as
weakness. Distal weakness was not described in any
of the initial evaluations, but was obvious in patients 3
and 4 at referral. Distal weakness was most notable in
the interosseous muscles of the hands.
Electrophysiologic studies. Each patient underwent at least 1 nerve conduction study and needle
examination. However, no patient displayed any abnormalities in nerve conduction. Each patient had
widespread fibrillations, positive waves, and myopathic motor unit potentials and all were interpreted as
being consistent with an inflammatory myopathy. One
study (patient 3) was considered atypical because it
failed to demonstrate a proximal-to-distal gradient of
myopathic changes.
Treatment. Each patient had been initially
treated for polymyositis over a period that ranged from
3 months to 6 years, and none had demonstrated
significant gains in strength or normalization of muscular enzyme levels. Treatment programs were heterogeneous , but consisted of high-dose prednisone
(40-60mg/day) in patients 1,2, and 3, and consisted of
a combination treatment Of intermittent courses Of
intravenous nitrogen mustard followed by prednisone
and low-dose methotrexate (7.5-10 mglweek) in patient 4.
Because their symptoms were presumed to be
Table 2. Clinical findings in 4 inclusion body myositis patients
~
Patient
Age/sex
Duration of
symptoms
(years)*
Duration of
treatment for
polymyositis
Distribution of
muscular
weaknesst
1
24@
1.5
6 months
Legs, neck, arms,
proximal only
Legs, neck then
arms, proximal
more than distal
Legs, arms, neck,
proximal more
than distal
Legs, neck proximal
more than distal
2
52lM
3 4
3 months
3
74lF
6
4 years
4
66lF
8
6 years
~~~~
~~
~
Laboratory resultst
ANF
ENA
DNA
ESR
CPK
Aldolase
1:320
Negative
Negative
14
3.5
1.5
Negative
ND
ND
6
2
Negative
Negative
Negative
6
2.5
1.5
Negative
ND
ND
5
4
1.5
ND
* Prior to diagnosis of inclusion body myositis.
t At the time of diagnosis of polymyositis.
$ ANF = antinuclear factor; ENA = extractable nuclear antigen (RNP, Sm, SS-B); ESR = erythrocyte sedimentation rate (mmhour); CPK
=
creatine phosphokinase; ND
=
not done. For CPK and aldolase, values are the highest observed (units are times the upper limit of normal).
IBM AS TREATMENT-RESISTANT PM
399
Table 3. Data from biopsy specimens from patients with inclusion body myositis (IBM)
Patient 1
Biopsy 1
Biopsy 2
Biopsy 3
Patient 2
Biopsy 1
Biopsy 2
Patient 3
Biopsy 1
Patient 4
Biopsy 1
Biopsy 2
Light microscopy
Electron microscopy*
Taking
medication at
time of biopsy
Initial
interpretation
Retrospective
interpretation
No
Yes
Yes
Polymyositis
Polymyositis
Polymyositis
Polymyositis
Polymyositis
IBM
ND
ND
ND
ND
IBM
ND
No
No
Polymyositis
IBM
IBM
IBM
ND
No IBM
ND
No IRM
No
Polymyositis
IBM
ND
IBMt
No
Yes
Polymyositis
Polymyositis
ND
IBM
ND
ND
ND
Initial
interpretation
Retrospective
interpretation
ND
* ND = not done
t Performed on frozen, stored material.
resistant to treatment, each patient had also been
treated with a variety of immunosuppressive regimens. Patient 1 received high-dose prednisone plus
cyclophosphamide (1-2 mg/kg), and high-dose
prednisone plus methotrexate (25-30 mg/week). Patient
2 received high-dose prednisone plus azathioprine (1-2
mg/kg). Patient 3 had been treated with lymphoplasmapheresis (16 treatments over a 12-week period). Patient 4 received high-dose preddisone plus methotrexate (25-30 mg/week). No significant improvement in
strength was noted in any patient, but while taking
methotrexate weekly, patient 1 maintained normal
levels of muscle enzymes for a prolonged period of
time.
The long-term outcome of this study group was
characterized by a gradual progression of muscular
weakness of the lower extremities, then the upper
extremities, and then the distal extremities. Three
patients remain ambulatory after 3 to 7 years of
followup, while 1 patient (patient 4) is mainly confined
to a wheelchair after a disease duration of more than
10 years.
Muscle biopsy. Eight biopsies were performed
on the study group, and all but 1 were available for
reevaluation. In 2 patients, fresh-frozen tissue was
available, but for all 4 patients, resin-embedded tissue
was available for examination by electron microscopy.
Table 3 shows the official interpretation of the
initial biopsy specimen, as reported on the pathology
form, as well as whether reevaluation of the same
slides detected the characteristic findings of IBM
(Figures 1, 2, and 3) (6). Table 3 also gives the therapeutic status of the patient at the time of diagnosis.
Each patient’s biopsy specimen revealed evidence of individual fiber destruction or regeneration,
as well as chronic inflammatory cells, with interstitial
inflammation ranging from mild to severe. Perivascular inflammation was observed in samples from 2 of the
patients.
DISCUSSION
Since the original description of IBM by one of
us (SMC) (l), numerous series of patients have been
described, detailing features which serve to distinguish
this nosologic entity as a distinct form of inflammatory
myopathy (2-5). Based on these case reports, it would
appear difficult to confuse IBM diagnostically with
idiopathic polymyositis. The studies by Carpenter et al
(3) have suggested that IBM is an extremely rare
disease. It was found in only 6 of 1,500 patients who
underwent muscle biopsy. In contrast with other inflammatory myopathies, IBM appears to have a bimodal age distribution, with its onset in the second and
sixth decade. Clinically, IBM has several features that
have distinguished it as a unique form of inflammatory
myopathy, including: distal, as well as proximal, muscle atrophy and weakness; mild or minimal elevation
of muscle enzymes; neuropathic findings by electrophysiologic studies; rare, or no, association with connective tissue disease or malignancy; and resistance to
high-dose corticosteroid thetapy .
Most importantly, the diagnostic pathologic
features of the “lined vacuole,” the large intranuclear
and intracytoplasmic inclusions by light microscopy,
and the characteristic microtubular elements observed
400
CALABRESEETAL
on the basis of being reevaluated as presumed
“polymyositis treatment failures” and, thus, may represent an important subset of patients with IBM. On
presentation, each of our patients lacked distal weakness and neuropathic changes on electrophysiologic
studies, features which clinically distinguish IBM as a
Figure 1. Biopsy sample from patient 1 , showing lymphocytic
infiltrate along thick myofibers, and 2 inclusions (arrows) in enlarged
nuclei (hematoxylin and eosin stained, original magnification X 490).
by electron microscopy should further differentiate
IBM as a specific disease.
We now believe that previous studies of IBM
may have been biased by
fact that they were
On the basis Of pathology and may therefore
represent the disease in its fully developed form.
Alternatively, our patients were all selected clinically
Figure 2. Transversely cut cryosections of myofibers from patient
1, showing typical lined vacuoles (black arrows) and smooth
vacuoles (white arrows) with vacuolated nuclei (hernatoxylin and
eosin stained, original magnification x 490).
IBM AS TREATMENT-RESISTANT PM
Figure 3. Biopsy specimen from patient 1 , showing a round area of intranuclear filamentous inclusions in an otherwise
normal-appearing sarcolemmal nucleus (original magnification x 21,800). Inset, Higher magnificationof the area within the
small rectangle, showing microtubular profiles with a central hole 5 nm in diameter (arrows) (original magnification x
109,OOO). Bar = 100 nm.
401
402
distinct form of inflammatory myopathy. And while
distal weakness, particularly of the interosseous muscles of the hands, evolved in all of them, none demonstrated abnormal results on nerve conduction studies, even years into their clinical course. Proximal
muscular weakness with mildly elevated muscle enzyme levels is common in idiopathic polymyositis, and
failure to improve with corticosteroid treatment may
also be observed in a sizable portion of patients (7).
Most perplexing in our cases was the fact that
each patient’s initial muscle biopsy specimen, and
even subsequent biopsy specimens, were all interpreted as being consistent with features of polymyositis. With this pathologic interpretation, each of our
patients fulfilled the diagnostic criteria of Bohan and
Peter for definite polymyositis (8). Important questions include why were the initial, and sometimes
subsequent, muscle biopsy specimens interpreted as
being consistent with features of polymyositis and not
with features of IBM, and did the initial diagnoses
represent more than incorrect pathologic interpretations? At least 3 possibilities must be considered.
First, the original biopsy specimen may have been
misinterpreted by the pathologist, either through lack
of recognition of the diagnostic changes or by overlooking the sometimes subtle pathologic features. Second, the lesions may have been patchy in nature and
the original biopsy may have not yielded the tissue that
had the diagnostic changes. Third and last, the characteristic histopathologic changes may appear more
florid, as a function of time or, possibly, as a complication of steroid therapy.
From our data, a combination of these factors
appear to explain the pathologic interpretation of
polymyositis and the failure to recognize the changes
of IBM. In patient 1, the features of IBM detected by
light microscopy were absent in the first and second
biopsy specimens, even on reexamination, but were
present when the second biopsy specimen was examined by electron microscopy (see Figure I). In patients
2, 3, and 4, the characteristic changes seen with light
microscopy were detected on review of the original
tissue. It should also be noted from these data that the
inclusions were identified in 2 patieats who were not
receiving drug therapy at the time of biopsy, which
suggests that lesions are not the result of therapy.
Furthermore, in 2 light microscopic studies, inclusions
were not identified even on review, and in patient 2,
were not detected by electron microscopy. Thus,
possible explanations for failure to diagnose IBM
pathologically, include a low index of suspicion or
CALABRESE ET AL
failure of recognition by the pathologist, the skip
lesion nature of the pathologic findings, and failure to
examine the tissue by electron microscopy.
Complicating the diagnostic process is the fact
that histopathologic confirmation of IBM is often
elusive. Characteristic findings may be present in only
a small percentage of fibers, and the recognition of
these findings may be difficult (7). The large eosinophilic nuclear or cytoplasmic inclusions of affected
fibers often will have a characteristic halo about them
in paraffin-embedded sections, but in cryosections, the
halo is absent and detection may be difficult. The
characteristic vacuoles lined with basophilic granules
on hematoxylin and eosin staining of cryosections
often lose their granular appearance and appear as
large empty vacuoles, rather than as distinctive lined
vacuoles, in paraffin sections. Thus, examination of
biopsy tissue as both cryosections and paraffin-embedded sections enhances the diagnostic process. Electron microscopy remains the standard for definitive
diagnosis with identification of the characteristic
microtubular filaments, but sampling problems may
limit this technique as exemplified in patient 2.
The histopathologic changes of IBM recently
have been associated with a variety of autoimmunelike conditions including Sjogrep’s syndrome (9),
thrombocytopenia (lo), and an ill-defined connective
tissue-like disease (11). The therapy for IBM has been
disappointing. There have been only 2 reported cases
of successful treatment with corticosteroids (1 1,12)
and no reports of successful immunosuppressive therapy. The recent observation that these inclusions stain
positively with an anti-mumps hetero-antiserum (13)
may further prompt more innovative treatment protocols, including anti-viral agents or interferon. At
present, we are treating all IBM patients with 3-4month regimens of high-dose corticosteroids (1
mg/kg), and if no response is observed, the corticosteroids are gradually tapered and discontinued.
We believe that IBM is a more frequently
encountered form of inflammatory myopathy than was
previously suspected. In addition to these 4 patients,
we are observing 6 cases of IBM that have been more
readily diagnosed over the past 4 years. We believe
that IBM should be strongly considered in any patient
with presumed treatment-refractory polymyositis, particularly when the disease is characterized by an
insidious course with marked quadriceps weakness
and atrophy and with minimal elevation of muscle
enzyme levels. Most useful, when present, is the
IBM AS TREATMENT-RESISTANT PM
patient’s inability to make a clenched fist; it is presumed that this is the result of weakness of the distal
arm and hand muscles. This is an unusual finding in
any inflammatory rnyopathy and appears to evolve in
nearly all patients at some point in their disease
course. To validate the diagnosis, we recommend first
that available tissues be reexamined, under light microscopy, for characteristic features which may have
been overlooked. Second, the tissues should be examined by electron microscopy when possible. If this is
unrevealing, a repeat biopsy at 2 sites (a proximal
upper and proximal lower extremity) is suggested,
with examination of both frozen and paraffin-ernbedded sections by light microscopy, and of appropriately
fixed tissue by electron microscopy.
The diagnosis of IBM remains a problem. This
is partially due to the lack of accepted diagnostic
criteria similar to those widely used in polyrnyositis
and dermatomyositis (8). We have proposed a set of
preliminary diagnostic criteria that rely on both clinical and pathologic features; these criteria may serve as
a starting point for further refinement as more is
learned about the scope of IBM. The criteria necessitate both pathologic and clinical findings for diagnosis.
We believe that the pathologic findings are based on
higher specificity for definite disease, as opposed to
lesser specificity for probable and possible disease.
The clinical criteria absolutely necessitate the presence of proximal muscle weakness of insidious onset,
as well as other potential clinical criteria. Numerous
other pathologic findings, such as “ragged-red” fibers
and clusters of atrophic fibers, have been reported in
IBM but we believe these are of significantly less
specificity and therefore should not be included as
diagnostic criteria ( 13). Exclusionary criteria similar to
those found in the classification of Bohan and Peter (8)
could be used; however, we feel that too little is
known about this increasingly recognized form of
myopathy for this to be a possibility. Further studies
403
are needed before definitive criteria can be established.
REFERENCES
1. Chou SM: Myxovirus-like structure in a case of human
polymyositis. Science 158: 1453-1455, 1967
2. Yunis EJ, Samaha FJ: Inclusion body myositis. Lab
Invest 25:240-248, 1971
3. Carpenter S, Karpati G , Heller I, Eisen A: Inclusion
body myositis: a distinct variety of inflammatory
myopathy. Neurology 28:8-17, 1978
4. Eisen A, Berry K, Gibson G: Inclusion body myositis
(IBM): myopathy or neuropathy? Neurology 33:
1109-1 114, 1983
5. Danon MJ, Reyes MG, Perwrena O H , Masdeu JC,
Manaligod JR: Inclusion body myositis, a corticosteroid
resistant inflammatory myopathy. Arch Neurol 39:
760-764, 1982
6. Chou SM: Inclusion body myositis, a possible chronic,
persistent muscle infection by mumps virus. Cleve Clin
Q 52~583-589, 1986
7. Kagen LJ: Polymyositis/dermatomyositis, Arthritis and
Allied Conditions. Tenth edition. Edited by DJ McCarty. Philadelphia, Lea & Febiger, 1985, pp 971-993
8. Bohan A, Peter JB: Polymyositis and dermatomyositis.
N Engl J Med 292:344-347, 403-407, 1975
9. Chad D, Good P, Adelman L, Bradley WG, Mills J:
Inclusion body myositis associated with Sjogren’s syndrome. Arch Neurol 39:18&188, 1982
10. Riggs JE, Schochet SS, Gutman L , McComas CF,
Rogers JS: Inclusion body myositis and chronic immune
thrombopenia. Arch Neurol 41 :93-95, 1984
11. Lane R, Fulthorpe JJ, Hudgson P: Inclusion body
myositis: a case with associated collagen vascular disease responding to treatment. J Neurol Neurosurg Psychiatry 48:270-273, 1985
12. Levin K, Mitsimoto H , Agamanolis D: Steroid responsiveness and clinical variability in inclusion body
myositis. Muscle Nerve 9:217, 1986
13. Chou SM: Inclusion body myositis: a chronic persistent
mumps myositis. Hum Pathol (in press)
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