Inclusion Body Myositis
Inclusion body myositis (IBM) is a disease causing progressive muscle weakness and atrophy for which no reliable effective treatment currently exists. It has been estimated to affect between 5 and 11 people per million. It is classified within a group of conditions known as inflammatory myopathies, named for the presence of cells of the immune system (“inflammation”) within muscle tissue as detected by the examination of muscle biopsy specimens under the microscope. In addition to inclusion body myositis, the other main categories of inflammatory myopathy are dermatomyositis and polymyositis.
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About Inclusion Body Myositis
The “typical” syndrome affects individuals over the age of 50; develops very slowly with a frequently delayed diagnosis an average of 6 years after onset of symptoms; affects proximal and distal muscles, with characteristic involvement of quadriceps, wrist and forearm finger flexors, and swallowing muscles; and has pathology characterized by the presence of: (1) prominent inflammatory cells (generally T cells and macrophages when they have been studied) surrounding and sometimes shown to be invading myofibers, (2) rimmed vacuoles, structures of uncertain nature, particularly in small angulated myofibers, (3) whorls of cytomembranous material of uncertain nature, (4) inclusions within myofibers, a proportion of which have immunoreactivity suggesting aggregated proteins folded into β-pleated sheets (“amyloid”), and (5) 15-21 nm tubulofilaments within cytoplasm and nuclei.
Research Diagnostic Criteria
Two sets of research diagnostic criteria for inclusion body myositis have been proposed. The Griggs et al. criteria allow for “Definite” and “Possible” diagnoses1; the European NeuroMuscular Center (ENMC) criteria allow for “Definite” and “Probable” diagnoses2. These criteria have been proposed for research purposes, and are not necessarily the ideal criteria for clinical diagnosis and management of patients.
We are aware of one comparison of these criteria2. For 103 patients with inclusion body myositis, 72 met ENMC for definite inclusion body myositis but only 16 met Griggs et al. criteria for definite inclusion body myositis, while 31 met ENMC criteria for probable inclusion body myositis and 87 met Griggs et al. critiera for possible inclusion body myositis. These criteria therefore differ substantially in their classification of definite inclusion body myositis patients.
There are a number of features of these criteria worth emphasizing. The Griggs et al. criteria include vacuoles, but do not require that they be rimmed vacuoles. Neither set of criteria specify the extent of the pathological features that need to be present for diagnosis, such as the minimum number of vacuoles or rimmed vacuoles that need to be present (i.e., is 1 vacuole on a 20 sq-mm cross-section sufficient?). In particular, non-rimmed vacuoles may be seen in frozen muscle sections as the result of freeze artifact and the first set of criteria do not consider this. Additionally, the criteria pertaining to invasion of non-necrotic muscle fibers by mononuclear inflammatory cells is also problematic; it is frequently unclear whether a cell “invades” or just contacts the sarcolemma of myofibers, and the criteria is not quantitative—so that one area of apparent invasion is sufficient. The specificity of this criteria is in doubt4.
None of the clinical or pathological features of inclusion body myositis are completely specific to it. The clinical pattern of forearm finger flexor weakness may occur in sarcoidosis and hereditary distal myopathies; inflammatory myopathy with T cells surrounding myofibers occurs in polymyositis5, 6; rimmed vacuoles occur in PABPN1-mutation related ocluopharyngeal muscular dystrophy (OPMD)7, genetically uncharacterized rigid spine syndromes7, other familial but not yet genetically characterized oculopharyngeal syndromes8, 9, fascioscapulohumeral muscular dystrophy10, hereditary inclusion body myopathy due to GNE mutations11, limb-girdle muscular dystrophy with reduced laminin b1 expression12, X-linked emerin muscular dystrophy13, 14, and neurogenic disorders7; cytomembranous whorls or myeloid bodies occur in early onset or familial inclusion body myopathies15, 16, hypokalemic periodic paralysis17 and OPMD; inclusions are present in nuclei in OPMD18, though of a different character and in nuclei and cytoplasm in an uncharacterized infantile disorder19; and 15-21 nm diameter tubulofilaments are present in OPMD20. At least one report has noted endomysial inflammation with GNE mutation related hereditary inclusion body myopathy21.
The first reported case of inclusion body myositis that distinguished this disease from other inflammatory myopathies was a detailed study by Chou in 196722. In this report, Chou reported careful light- and electron-microscopic pathological observations of the disease. The term “inclusion body myositis” was applied in 197123 in a case report of a patient who, in light of current knowledge, probably did not have the disease, but had instead an hereditary inclusion body myopathy, possibly due to a mutation in the GNE gene. This patient had onset of leg weakness at age 18, and when examined by the authors at age 26, had a lordotic posture with lower extremity limb girdle weakness and no weakness or atrophy of the quadriceps. Inflammation present on the biopsy was not well characterized.
“Typical” clinical features observed in case series and reported in review articles are the ones emphasized in the Griggs et al. diagnostic criteria (Table 1). A recent cross-sectional study of 64 patients in the Netherlands fulfilling ENMC criteria for “probable inclusion body myositis” provides the most detailed information available about several clinical features24. In addition to confirming the commonly held clinical view of inclusion body myositis has a slowly progressive disease with asymmetric weakness that is most prominent for quadriceps, wrist flexors, and deep > superficial finger flexors, and least prominent for limb girdle and intrinsic hand muscles, additional observations were emphasized. Onset occurred as early as age 39, with 20% of patients having onset prior to age 50. At the time of the study, patients studied had symptoms for an average of 10 (male) to 14 (female) years. Dysphagia was present in 66% of patients; 73% of patients used an assistive device for walking; 14% of patients used a wheelchair intermittently; 3% of patients were entirely dependent on a wheelchair; no patient had stopped working prior to retirement at ages 60-64. Six percent of patients had serum CK greater than 12 times the upper limit of normal.
A study of 78 patients looked specifically at ambulation status and found that the duration of time from symptom onset to use of a walker was dependent on age; for onset between age 40 and 49 years, it was a mean of 17 years before use of a walker; for age 50-59, 8.3 years; for age 60-69, 6.8 years; and for age 70-79, 3.2 years25.
Spectrum of Disease
Inclusion body myositis has been reported in association with other diseases, including malignancy26, systemic autoimmune diseases27, connective tissue diseases28, 29, HIV infection30, HTLV-1 infection30-32, sarcoidosis33, 34, emerin mutation Emery-Dreifuss muscular dystrophy14, and a not fully characterized congenital myopathy19. Some of these cases have been atypical. One report with HTLV-1 infection had fiber type grouping and no inflammation and would not meet research criteria for definite, probable, or possible inclusion body myositis35. The pathological findings including rimmed vacuoles could be the result of anterior horn cell degeneration in this case.
The pathology of inclusion body myositis has been characterized by the presence of: (1) prominent inflammatory cells (generally T cells and macrophages when they have been studied) surrounding and sometimes shown to be invading myofibers, (2) rimmed vacuoles, structures of uncertain nature, particularly in small angulated myofibers, (3) whorls of cytomembranous material of uncertain nature, (4) inclusions within myofibers, a proportion of which have immunoreactivity suggesting aggregated proteins folded into b-pleated sheets (“amyloid”), (5) 15-21 nm tubulofilaments within cytoplasm and nuclei, and (6) variable degrees of so called “mitochondrial abnormalities”. We discuss each of these in turn.
Most patients with inclusion body myositis are not enrolled in research studies and not all laboratory pathology departments routinely look at the cell types present in muscle biopsy. Rather, the mononuclear cells seen on hematoxylin and eosin (H&E) and modified Gomori trichrome staining are usually interpreted as “inflammatory cells”.
The nature of the inflammatory cells present in inclusion body myositis and more generally inflammatory myopathy and Duchenne muscular dystrophy muscle was studied in a series of publications by Arahata and Engel 20 years ago5, 6 and 36-38. These seminal studies were quantitative and defined relative proportions of cells with various cell markers in these diseases. Immunohistochemical methods using antibodies directed against cell markers believed to be sensitive and specific at the time for various populations of T cells, B cells, macrophages, and natural killer (NK) cells were used.
The generally accepted view reflected in texts and review articles39, 40, is that cytotoxic T cells, identified by microscopy via their high expression of CD8, are the most important type of infiltrating cell in inclusion body myositis muscle (see T cell images). However, analysis of serial adjacent sections suggests that typically less than 50% of the T cells present express CD8. The nature of these additional T cells are unclear; some of them are likely T helper cells, as defined by the expression of CD4. However, CD4 is also highly expressed on dendritic cells. Many of the CD4+ cells present in muscle in the inflammatory myopathies are not T cells, but are dendritic cells instead.
Although B cells have been considered to be sparse in inclusion body myositis and PM muscle and unimportant to the disease mechanism for over 20 years, their differentiated form — plasma cells — are sometimes abundant41. Plasma cells function as antibody secreting cells, and this finding suggests that the antibody producing arm of the adaptive immune system is involved in these diseases. We have demonstrated from molecular analysis of antibody genes that there is likely antigen-driven B cell development and antibody production in inclusion body myositis, PM, and DM muscle.
Rimmed vacuoles are holes (vacuoles) within myofibers that are lined with blue granular material on H&E stains or red material on trichrome stains. Their presence is a “hallmark” feature of inclusion body myositis. Rimmed vacuoles in inflammatory myopathy are not unique to inclusion body myositis; we have seen them in steroid-responsive dermatomyositis and polymyositis and others have seen them in polymyositis as well, noting that inclusion body myositis seems to be distinguished by a greater number of rimmed vacuoles present than in these other disorders42. Rimmed vacuoles are seen in a number of other neuromuscular disorders, including muscle and long-standing chronic nerve diseases. Their nature is uncertain, but generally accepted to be of “lysosomal origin”. The earliest work on inclusion body myositis emphasized the degeneration of myonuclei in association with rimmed vacuoles46, and we believe their formation is indeed closely associated with the degradation of myonuclei. Most rimmed vacuoles contain nuclear membrane proteins present within the rim.
Approximately 70 proteins have been reported as abnormally accumulated near rimmed vacuoles or independently within myofibers in immunohistochemical studies. These findings have contributed to models of inclusion body myositis as involving dysfunction of the ubiquitin proteasome system43, 47.
Cytomembranous whorls are generally reported with examination of glutaraldehyde fixed specimens by electron microscopy (see image). The larger cytomembranous whorls are also apparent on glutaraldehyde fixed toluidine blue “semithin” sections viewed under light microscopy (see image), and it is likely that the some of the blue granular material seen in the rim of rimmed vacuoles lie within these structures. These structures are of unknown origin and have generally been reported as present near or within vacuoles44, 45. Chou reported additionally that they developed near nuclei, and were not present unless there were also tubulofilaments present in myofiber cytoplasm46.
The term inclusions, or inclusion bodies, initially refered to multiple circular coalescing red (“eosinophilic”) structures seen infrequently in myofibers on H&E stains. The term has subsequently been applied to a variety of structures present and associated with vacuoles, including the tubulofilaments seen on electron microscopy. One research group has distinguished two types of inclusions present in inclusion body myositis: a rounded inclusion with immunoreactivity to amyloid-β and containing 6-10 nm diameter fibrils; and a squiggly linear inclusion with immunoreactivity attributed to tau containing 15-21 nm paired helical filaments or tubulofilaments47. The interpretation that these filaments contain tau has been based on immunohistochemical studies using the SMI-31 antibody but this antibody is not specific to tau and reacts to a number of other filaments and proteins.
The presence of tubulofilaments has generally been taken to be a highly specific feature of inclusion body myositis. These structures are seen only on electron microscopy (though one report stated that these could be seen with light microscopy)23, are of an approximate 15-21 nm in their diameter, and are of uncertain nature. Chou hypothesized based on his observations that they developed initially within myonuclei and Karpati and Carpenter made supportive observations. Mhiri48 reported inclusions composed of tubulofilaments in the sarcoplasm usually lying in the vicinity of membranous whorls filling the rimmed vacuoles. Collective, there is substantial evidence that rimmed vacuoles, cytomembranous whorls, inclusions, and tubulofilaments are all structures seen, with different methods of visualization, in close association with each other. We have generally seen tubulofilaments within nuclei.
The lack of efficacy of immunosuppressive or immunomodulatory treatment for inclusion body myositis has been repeatedly emphasized in case series and reviews of this disease. It is remarkable that inclusion body myositis is relatively resistant to immunotherapies despite its marked inflammation believed to be of an identical nature to that of polymyositis39, a disease that generally responds readily to immunotherapy. We are aware of only a single difference that has been recognized in the nature of the immunological response occurring in these two diseases. In inclusion body myositis, there was more frequent invasion of non-necrotic muscle fibers and more endomysial cells present than in PM38.
Several treatment trials have been performed. One study of 37 patients used IVIG+prednisone compared to placebo+prednisone49. This trial used a combination of IVIG 2 gm/kg/month for 3 months together with prednisone 60 mg/day x 1 month and then tapering of this dosage to 60 mg every other day by the end of 3 months. This trial found no clinical benefit of IVG+prednisone over placebo+prednisone. Pre- and post-study muscle biopsies showed found significant reductions in the percentage of necrotic muscle fibers with IVIG+prednisone treatment, but not prednisone alone treatment, and reductions in the numbers of CD2+ cells in both groups (Table 4). This study viewed CD2+ cells as T cells though natural killer cells and some dendritic cells express CD2 as well.
Another important treatment study looked at the clinical and pathological response in 8 patients with inclusion body myositis to approximately 6 months of treatment with high dose prednisone50. This unblinded and uncontrolled study found progression of muscle weakness despite reduction in serum CK (mean of 819 IU/L pre-treatment and 197 IU/L post-treatment), and reduction in the number of non-necrotic myofibers invaded by mononuclear cells. The numbers of vacuolated fibers and Congo Red positive fibers increased during treatment. A study of 44 patients randomized to methotrexate 5-20 mg/week or placebo found no significant decline in the rate of progression of weakness in 48 patients with inclusion body myositis over 48 weeks of treatment51.
An unblinded study of 11 patients with prednisone + azathioprine + oral methotrexate compared to prednisone + IV methotrexate for 3-6 months was performed52. The diagnostic criteria for this study was limited and stated to be only the presence of rimmed vacuoles on muscle biopsy. Of 21 treatments applied in this crossover study, 3 improvements and 11 stabilizations were noted; the implications of stabilization could not be determined without prior disease course indicated. There is additionally anecdotal evidence of the refractoriness of inclusion body myositis to immunosuppressive treatment from several publications that did not directly study treatment. One study, focused on the frequency of different types of abnormal myofibers present in muscle biopsy specimens, included 11 subjects all of whom had progression of weakness despite treatment with prednisone plus additional varying combinations of azathioprine, methotrexate, and cyclosporine53. In another study, of 29 patients treated with at least 40 mg/day of prednisone for 3 months, several patients reported temporary arrest of disease progression and 1 patient improved in muscle strength at 5 months. Twenty-five of these patients were observed for 2 or more years; all showed progression of weakness44.
Additional case reports also note occasional response to treatment of patients with inclusion body myositis. A patient with SLE and secondary Sjogren’s syndrome developed an inflammatory myopathy with rimmed vacuoles and intranuclear and cytoplasmic 12-20 nm tubulofilaments, meeting criteria for definite inclusion body myositis. This patient responded to treatment with prednisone and methotrexate with recovery of strength28. Another case of SLE and subsequent development of definite inclusion body myositis also responded to therapy with IVIG after refractoriness to prednisone29.
A review of experience with 32 patients with inclusion body myositis at the Cleveland Clinic was reported in 1992. Clinical improvement with immunosuppressive therapy was rare, but the authors felt that combination therapy, with prednisone plus methotrexate, azathioprine, or cyclosporine was associated with a slower rate of disease progression54.
Two patients were reported stabilized by treatment with prednisone and monthly IVIG at 39 and 45 months of followup55.
One patient with a steroid resistant myopathy classified as inclusion body myositis has been reported responding to treatment with chlorambucil56. Finger and wrist flexor and quadriceps strength was not reported, the patient had scarce 16 nm filaments in cytoplasm, considered atypical of EM findings in inclusion body myositis, and had a serum CK of 5200 U/l. It is uncertain then whether this patient actually had inclusion body myositis.
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