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Synopsis of Dalakas 2006 article

I have tried to present some of the key excerpts from this excellent review article. I have removed the reference numbers to make it less confusing. I have also left out most of the diagrams. I have focused on points that I think would be helpful to the average patient and left out a fair bit that would be pertinent to the physician, for example some of the microscopic features. Please refer to the original article for a more complete understanding.

Reference: Dalakas, MC (August, 2006) Sporadic inclusion body myositis - diagnosis, pathogenesis and therapeutic strategies.Nature Clinical Practice Neurology 2: 437-447.

INCLUSION BODY MYOSITIS OVERVIEW

INTRODUCTION:
. . . sIBM is a slowly progressive myopathy that affects proximal and distal muscles, and has a distinctive histopathology characterized by autoimmune inflammatory features combined with degenerative features, such as vacuoles, filamentous inclusions (hence the term inclusion body myositis) and accumulation of amyloid-related proteins.

sIBM is often misdiagnosed as polymyositis or other diseases, and is frequently only suspected retrospectively when a patient with presumed polymyositis does not respond to therapies.

sIBM is the most common acquired myopathy in patients above the age of 50 years, and it affects men slightly more often than it does women. Its prevalence is estimated at between 4.3 and 9.3 per 1,000,000, rising to 35.3 per 1,000,000 for people over the age of 50 years.

sIBM causes weakness and atrophy of the distal and proximal muscles, and involvement of quadriceps and deep finger flexors are clues to early diagnosis. Patients often present with falls because their knees collapse owing to quadriceps muscle weakness, or with difficulty performing certain tasks, such as turning keys, tying knots and holding golf clubs, owing to weakness of finger flexors.

Dysphagia occurs in up to 60% of patients with sIBM, leading to choking episodes.

DIAGNOSIS
Creatine kinase levels can initially be elevated up to 10-fold, but they remain only slightly elevated as the disease progresses.

Muscle biopsy is essential for diagnosis: from the outset, there are signs of chronicity characterized by hypertrophic, atrophic and split fibers with internal nuclei and increased connective tissue, indicating that the disease process has begun long before the patient seeks medical attention.

If a patient has the typical clinical phenotype of sIBM, but the muscle biopsy shows only features of a chronic inflammatory myopathy (inflammation, large fibers, splitting, and increased connective tissue, but no vacuoles), the diagnosis is probable sIBM. If, however, there is also strong upregulation of major histocompatibility complex (MHC) class I antigens, and amyloid deposits and cytochrome-oxidase-negative fibers are present, the diagnosis of sIBM is rather more certain.

Shaking hands with a patient can provide the first indication of sIBM, because of the weak grip. If the patient complains of falls due to weakness at the knees and feet, has atrophic thighs, and does not report paresthesias or cramps, sIBM is very likely. Diagnostic dilemmas arise when the weakness and atrophy are slightly asymmetric or limited to the lower extremities, raising the possibility of a lower motor neuron disease. Motor neuron disorders, however, can be distinguished from IBM by the presence of hyper reflexia, cramps, fasciculations and large motor units on EMG. sIBM is most often misdiagnosed as polymyositis, based on the simplistic view that creatine kinase elevation with endomysial inflammation denotes polymyositis.

Disease progression is slow but steady, and resembles that of a dystrophy. Most patients with sIBM require an assistive device, such as a cane, walker or wheelchair, within several years of onset. . . . At present, sIBM remains a disabling disease, with most patients requiring an assistive mobility device within 5 to 10 years of onset. In general, the older the age of onset, the more rapidly progressive is the course.

TYPES:

GENETICS
Genetic factors are presumed to play a role in sIBM, on the basis of an association between sIBM and certain human leukocyte antigen (HLA) genes, especially the DRb1*0301 and DQb1*0201 alleles. Alleles of the 8.1 ancestral haplotype in the center of the MHC class II region seem to confer susceptibility to IBM. The B8-DR3-DR52-DQ2 haplotype is found in 67% of sIBM patients, similar to the frequency of this haplotype in myasthenia gravis. The B8-DR3-DR52-DQ2 haplotype is also associated with earlier disease onset, indicating that immuno regulatory genes are inherently connected with the manifestation of symptoms.

[In addition to the sporadic type with its probable genetic predisposition pattern, there are also several types that are specifically linked to genetic causes and that are inherited from generation to generation. These are described as the] hereditary inclusion body myopathies (hIBM), a heterogeneous group of non-inflammatory, inherited syndromes. A subset of hIBM that spares the quadriceps muscles results from mutations in the GNE gene.

AUTOIMMUNE FEATURES
Evidence for an autoimmune basis for sIBM is supported by numerous observations (Box 1):

Box 1

Factors supporting an immunopathogenic disease mechanism for sporadic inclusion body myositis.

1 Immunogenetic association with DRb1*0301, DQb1*0201 alleles and the B8-DR3-DR52-DQ2 haplotype
2 DQ2 haplotype; the human leukocyte antigen (HLA)-A haplotype is associated with earlier disease onset
3 Occurrence of sporadic inclusion body myositis (sIBM) in family members of the ssame generation (familial inflammatory IBM), as seen with other autoimmune disorders
4 Association with other autoimmune disorders and autoantibodies
5 Association with paraproteinemia at a significantly higher frequency than in age-matched controls (22.8% vs 2%)
6 Association with common variable immunodeficiency and natural killer cells
7 Association with HIV and human T-lymphotropic virus (HTLV)-1 infection (13 cases reported to date)
8 CD8+ autoinvasive T cells surround major histocompatibility complex (MHC) class I-expressing fibers, express perforin and activation markers of cytotoxicity, and are clonally expanded
9 Ubiquitous upregulation of MHC class I antigen and costimulatory molecules on muscle fibers, even those not invaded by T cells; the counter-receptors of the costimulatory molecules are overexpressed on the autoinvasive T cells
10 Strong upregulation of cytokines, chemokines and their receptors at the protein, messenger RNA and gene level

sIBM is associated with paraproteinemias in up to 22.8% of patients-much greater than the 2% frequency found in age-matched controls-indicating disturbed immunoregulation. [Paraproteinemias: A group of related diseases characterized by an unbalanced or disproportionate proliferation of immunoglobulin-producing cells, usually from a single clone. These cells frequently secrete a structurally homogeneous immunoglobulin (M-component) and/or an abnormal immunoglobulin. Amyloidosis Multiple Myeloma, Cryoglobulinemia, POEMS Syndrome.]

The autoinvasive T cells are driven by specific, but still unidentified, antigens.. . . Further studies are needed to identify the antigens that trigger T-cell activation

Muscle fibers do not normally express MHC class I antigens. In sIBM, however, MHC class I is ubiquitously expressed even on muscle fibers remote from the inflammation.

VIRUSES
Viruses as possible triggering factors
Although paramyxoviruses and mumps have been indirectly associated with sIBM, molecular techniques have failed to confirm their presence in muscle. The best evidence points towards a connection with retroviruses. At least seven HIV or human T-lymphotropic virus (HTLV)-1-positive patients with sIBM have been reported, and we have seen six more cases in the past 3 years, indicating that the disease might be more common in patients who live longer . . . The disease is triggered by clonally driven subpopulations of activated CD8+ cells that expand in situ and invade muscle fibers expressing MHC class I, as seen in retrovirus-negative polymyositis and sIBM. These cells are retrovirus-specific, because their CDR3 region contains amino acid residues that are specific for viral peptide bound to HLA molecules. The retroviral infection, combined with immune recognition of the retrovirus, is sufficient to trigger the inflammatory process.

INFLAMMATION AND DEGENERATION IN INCLUSION BODY MYOSITIS
[There is clear evidence that in sIBM, the muscle cells degenerate: this is shown by the abnormal protein features. Dalakas points out that such degeneration is also seen in other muscle diseases.]
Evidence for a degenerative process in sIBM is provided by the presence of vacuoles (almost always in fibers not invaded by T cells) and the intracellular deposition of Congo-red-positiveamyloid and b-amyloid-related molecules (e.g. b-APP, phosphorylated tau, presenilin-1, apolipoprotein E, g-tubulin, clusterin, a-synuclein, gelsolin), and oxidative stress proteins. These accumulations are not unique to sIBM, and they are observed to a similar extent in other vacuolar myopathies.

STRESS ON THE ENDOPLASMIC RETICULUM (ER)
. . . the chronic upregulation of MHC class I exerts a stressor effect in the endoplasmic reticulum (ER), which might lead to a self-sustaining T-cell response.

The ER maintains quality control by processing, folding and exporting MHC molecules loaded with antigen.

In sIBM, the muscle fibers are overloaded with MHC molecules, and the antigenic peptides might not undergo proper conformational change to bind to the MHC class I complex, leading to ER stress and further protein misfolding.

CAUSES
sIBM is a complex disorder, the underlying cause of which is unclear. The observation that the intact muscle fibers are invaded by T lymphocytes, whereas the vacuolated fibers lack T-cell autoinvasion but show strong expression of MHC class I antigens, has led to the suggestion that two processes might occur in parallel: a primary immune process due to T-cell-mediated cyto toxicity, and a non-immune process character ized by vacuolization and intracellular accumulation of amyloid-related molecules, probably due to MHC class I-induced stress. An interplay between inflammatory mediators and stressor or degenerative molecules is likely.

SUMMARY OF CAUSAL MECHANISM
Accordingly, the following mechanism for the pathogenesis of sIBM can be proposed. Triggering factors, possibly viruses, could initiate the process leading to clonal expansion of T cells and T-cell-mediated, MHC class I-restricted cytotoxicity via the perforin pathway (Figure 4). The released cytokines upregulate MHC class I molecules, which cannot exit the ER, resulting in increased levels of the 'MHC-peptide-loading complex', and an ER-stress response. The ER stress results in accumulation of misfolded amyloid-related glycoproteins and activation of the transcription factor NFkB, both of which promote expression of inflammatory-mediator genes for cytokines and chemokines, thereby further stimulating the MHC/CD8 complex and inducing a self-sustaining inflammatory response. Such crosstalk between inflam matory and degenerative processes is supported by recent observations that in sIBM muscles there is a linear relationship between the messenger RNA (mRNA) level of cytokines and chemokines and that of b-APP, Tau and ubiquitin. Furthermore, in human myotubes, cytokines enhance the expression of b-APP, tau and ubiquitin mRNAs. Additionally, in the muscles of individuals with sIBM, cytokines such as IL-1b, TGF-b and metalloproteinases co-localize with MHC class I and b-amyloid (J Schmidt and MC Dalakas, unpublished observations). Recent observations that autophagic vacuoles and protein aggregates accumulating in perinuclear inclusions, called aggresomes, are sites of viral replication, and that certain viruses induce the formation of aggresomes, provide credence to the view that viruses could be potential triggers of sIBM, a condition in which aggresomes and autophagic vacuoles are prominent.

TREATMENT STRATEGIES
Despite the involvement of primary immune factors in the pathogenesis of sIBM, this disease remains resistant to most immunotherapies.

The response of dysphagia to intravenous immunoglobulin can be significant.

New biologic agents targeting the main immuno pathological processes such as T-cell proliferation, transmigration, antigen recognition or ER stress, might produce more rewarding results.

. . .the results of a 12-month, open, randomized trial in 11 sIBM patients using anti-T-lymphocyte globulin (ATG), have been encouraging, because increased strength was noted in the ATG group. A study using alemtuzumab, a T-cell-depleting monoclonal antibody against CD52, is currently in progress at the National Institutes of Health (MC Dalakas, Principal Investigator). Alemtuzumab is an even stronger agent than ATG, because it causes lymphocyte depletion for at least 6 months.

CONCLUSION AND KEY SUMMARY POINTS
sIBM remains a challenging muscle disease in which inflammatory features coexist with degeneration. Although evidence indicates that there is interplay between the inflammatory mediators associated with T-cell cytotoxicity and the degeneration-associated molecules, it is unclear what triggers the T cells to invade muscle fibers, how the vacuoles are formed, and what role the intracellularly accumulated amyloid-related proteins have. Most remarkably, it remains a mystery why sIBM does not respond to immunotherapies in spite of the primary role of cytotoxic T cells in forming immunological synapses with the muscle fibers, and the strong upregulation of cytokines, chemokines and costimulatory molecules. Further studies are needed to identify the antigens that trigger T-cell activation, the pathogenic role of intracellularly accumulated proteins, and the molecular events that lead to cell stress, misfolding of glycoproteins and vacuolation.

KEY POINTS
=Sporadic inclusion body myositis (sIBM) is a slowly progressive myopathy that affects proximal and distal muscles; its histopathology is characterized by autoimmune inflammatory features combined with degenerative features
= Involvement of quadriceps and deep finger flexors are clues to early diagnosis; neck flexors and extensors are also frequently affected
= The clinical diagnosis of sIBM is confirmed by muscle biopsy, and is aided by electromyography and determination of serum muscle enzyme levels
= The cause of sIBM is unclear, but two processes-one autoimmune and the other degenerative-appear to occur in parallel
= Several cases of sIBM have been seen in association with retroviral infections, indicating that a chronic persistent viral infection might be a potential triggering factor
= Despite the involvement of primary immune factors in the pathogenesis of sIBM, this disease remains resistant to most immunotherapies; a study using alemtuzumab, a T-cell-depleting monoclonal antibody, is currently in progress


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