Inclusion Body Myositis (IBM).

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Information About IBM.

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Part 1: Primary Information on IBM.

Part 2: Some Specific IBM Issues.

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Part 1: Primary Information on IBM.

The following information is fairly challenging, complicated and comprehensive. I suggest that patients read through the PDF overview linked below before going through this page.

My thanks to Robert W. Albrecht for his comments.

An overview of Inclusion Body Myositis in everyday language [Revision: August 2009].

Greek Letters Used: α (alpha) β (beta) γ (gamma) δ (delta) ε (epsilon) λ (lambda)

• 1-1 Basic information on sIBM.
•    A). Overview and symptoms.
•    B). Lifestyle impacts.
•    C). The course, incidence and prevalence of sIBM
•    D). Fact sheets.
•    E). Genetics.
•    F). BOX: Some basic terminology and relevant abbreviations.

• 1-2 The current classification of IBM.
•    A). Classification of the Myositis Forms.
•    B). Classification of the Myopathy (Inherited) Forms.
•    C). Idiopathic inflammatory myositis or idiopathic inflammatory myopathies.
•    D). Sporadic inclusion body myositis versus Polymyositis.
•    E). BOX: Terms and types of disease transmission/ acquisition that we need to differentiate.

• 1-3 Diagnosis.
•    A). How is it diagnosed?
•    B). Diagnostic criteria of sIBM.
•    C). Ambiguity of a Myositis Diagnosis.
•    D). The importance of a biopsy in sIBM.

• 1-4). Causes and Abnormalities.
•    A).  Synopsis of abnormalities seen in sIBM.
•    B).  Synopsis of possible causes of sIBM.

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Part 2: Some Specific IBM Issues.

• 2-1). Possible Complications.
•    A). Dysphagia.
•    B). Respiratory Complications.
•    C). Falls.
•    D). Lifestyle Complications.

• 2-2). sIBM and Peripheral Neuropathy.
• 2-3). sIBM and Prion Protein.
• 2-4). Exercise and sIBM.
• 2-5). sIBM as an immunological versus a neurological / neuromuscular disease.
• 2-6). sIBM and Alzheimer disease.
• 2-7). sIBM as an age related disorder.
• 2-8). The Major Histocompatibility Complex (MHC).
• 2-9). IBM and HIV Related Viruses.
• 2-10). open
• 2-11). Wikipedia entry for sIBM.
• 2-12). Cholesterol and sIBM.
• 2-13). My personal story.
• 2-14). Webpage References.

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1-1). Basic information on sIBM.

1-1 A). Basic overview and symptoms.

• Sporadic inclusion body myositis [MY-oh-sigh-tis] (sIBM) is a rare disease of the skeletal muscle cells.
• sIBM is a progressive disease: as more and more cells die off, the muscles become progressively weaker and shrink.
• sIBM has two major aspects:
  • sIBM is now often described as primarily an autoimmune disorder, the muscle cells display antigen flags on their surface that trigger the immune system to kill the cells. Inflammation is a prominent feature of the disease - myositis means inflammation of the muscle.
  • sIBM also involves degeneration of the muscle cells, characterized by major abnormalities of the proteins inside the muscle cells: abnormal proteins lump together into "inclusions" or inclusion bodies, hence the disorder's name.
• Dalakas, 2006, says "we can say that two processes, one autoimmune and the other degenerative, occur in the muscle cells in parallel." "Both of these processes have a role in the disease process but which one occurs first and which has the dominant role is still debated " (Needham and Mastaglia 2007).
• sIBM is not considered a fatal disease (baring complications - mostly dysphasia, generally speaking, sIBM will not kill you).
• sIBM is slightly more common in men than women.
• sIBM is an age-related disease, as we get older, it gets more and more common, it usually appears after the age of 50 and is the most common muscle disease in people over 50, however, about 20% of sIBM cases first present symptoms in their forties.
• sIBM is a rare disease, currently diagnosed in about 15 people per million overall. Numbers increase dramatically in older populations-about 50 cases per million in people over 50. Needham et al (2008).
• In the past, sIBM was usually considered a "painless" disease, however, IBM patients often report severe pain and muscle tenderness and this aspect is being recognized more today. As muscle weakness develops, patterns of movement change and this can cause a lot of soreness and stiffness in the body.
• There is currently no effective treatment available.
• Main points of a recent (2007) review of sIBM by Needham and Mastaglia:
  • Needham and Mastaglia (2007) list three major problems:
    • inflammatory changes: muscle fibres express MHC-I and show invasion by CD8+ lymphocytes;
    • cytoplasmic and intranuclear inclusions containing amyloid (beta) and several other Alzheimer-type proteins;
    • and segmental loss of cytochrome c oxidase (COX) activity in muscle fibres, which is associated with the presence of clonally expanded somatic mitochondrial DNA (mtDNA) mutations.
  • "Both of the first two processes have a role in the disease process but which one occurs first and which has the dominant role is still debated" (Needham and Mastaglia, 2007).
  • sIBM is apparently not caused by one genetic mutation but it has a clear genetic association - the association of sporadic inclusion body myositis with a set of genes (DR3-HLA-DR3, the 8·1 MHC ancestral haplotype) is one of the strongest HLA-disease connections recorded: it is present in ~75% of sIBM cases. (Needham and Mastaglia, 2007)
  • "Although sporadic inclusion body myositis usually presents after the age of 50 years, symptoms can start up to 20 years earlier. The most common reasons for presentation are related to weakness of the quadriceps muscles, such as difficulty rising from low chairs or from the squatting or kneeling positions (eg, when gardening), walking up or down stairs, and climbing ladders. Some patients with sporadic inclusion body myositis only present when they have severe weakness and atrophy of the quadriceps muscles and consequently start to have falls. Other common problems include di. culty in gripping, lifting, and using handheld tools or household implements (eg, spray cans or perfume sprays) due to weakness of the finger flexors" (Needham and Mastaglia, 2007).
  • "Sporadic inclusion body myositis is a relentlessly progressive disorder: most patients require a walking aid after about 5 years and the use of a wheelchair by about 10 years. This protracted course has made the results of drug trials difficult to interpret because few trials have been of adequate duration or have had sufficient power to detect even slight treatment effects" (Needham and Mastaglia, 2007).
  • "Experience shows that most patients do not to respond to the anti-inflammatory, immunosuppressant, or immunomodulatory drugs that are available, and there is no established therapy to stop the progression of the disease. A small proportion of patients do respond to treatment - at least initially - but, so far, there are no reliable markers for identifying them. The treatment of newly diagnosed cases is, therefore, largely empirical and varies considerably in different centres: in some centres, the above forms of therapy are not used, whereas in others, such as our own, an initial 3-6 month trial of prednisolone and an immunosuppressive drug (eg, methotrexate or azathioprine) is recommended. This treatment is particularly beneficial for patients with an associated connective tissue disease or other autoimmune disorders; in our experience, these patients are the ones most likely to respond. In addition, intravenous immunoglobulin therapy might be helpful in selected patients with severe dysphagia or rapidly progressing leg weakness" Needham and Mastaglia (2007).
• see references at the bottom of the page. Webpage References.

What does it do to me?

• How sIBM affects you will likely be quite variable, depending partly upon at what age you develop symptoms and the rate of progression of the disease in you. Askanas and Engel (2006) say "although there is a common pattern of weakness, it is important to note that to some degree, everyone is affected in slightly different ways, to different degrees and at different rates". Because the presentation of the illness is fairly unique, it is hard to compare yourself to anyone else-- there is not really an "average" case or to a "textbook" case.
• The first muscles affected can vary but are either usually those of the wrists and fingers, those that lift the front of the foot, or the muscles in the front of the thigh. Some patients notice major effects in the legs first while others notice weakness in the hands and arms first.
• sIBM tends to cause weakening of certain muscles in the body (see diagram below), both in the distal and proximal skeletal muscles. The 4 quadriceps muscles (the Vastus Medialis, Vastus Intermedius, Vastus Lateralis and the Rectus Femoris) in the front of the thighs are commonly affected first (and are often used for biopsy). Patients often complain of falls caused by their knees collapsing or due to the weakness in their legs: this weakness also causes major problems in getting out of a chair, getting up off of the floor, climbing stairs and stepping up onto curbs. Many patients also report that they have balance problems and easily "lose their balance" and fall (the muscles cannot compensate once the body starts to "tip over").
• Because sIBM also makes the lower leg muscles weak and unstable, people are very vulnerable to injury from tripping and falling down due to toe drop - the toe is not raised high enough when taking a step.
• There is also usually early and severe involvement of the deep finger flexor, and wrist flexor muscles. Hence, loss of finger dexterity and grip strength is a common presenting symptom or a prominent symptom. This makes it hard to make a tight fist, to take the tops off of bottles and to open doors. This is another common and distinct characteristic of sIBM. Dalakas, 2006 notes that you can often see the first symptoms of sIBM when shaking hands with the patient.
• Mobility is progressively restricted: it becomes hard to bend down, to reach for things, to walk (risk of tripping, stubbing one's toe, is greatly increased), to turn over in bed, get in and out of cars, etc.
• Most patients will need to progress to using a cane (for balance), a walker or rollator and finally, many people eventually need to use a scooter (not recommended) or a wheelchair.
• IBM will often lead to major or "total disability" within 10 to 15 years of symptom onset.
• "In general, the older the age of onset, the more rapidly progressive is the course" (Dalakas, 2006).
• Not all of the muscles in the body are affected, for example, the heart is not affected nor are the muscles in the digestive track (these muscles are of a slightly different type).
• The muscles involved in respiration are rarely affected (a handful of cases reported - see 2-1) but this aspect may be underestimated.
• Many patients will experience a feeling of weakness in swallowing, a condition called dysphagia. This condition can cause complications when "food gets stuck halfway down or goes down the wrong way" and choking results.

The following diagram presents the typical pattern of muscle weakness seen. [From: http://www.mda.org/publications/fa-myosi-qa.html]

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1-1 B). Lifestyle Impacts.

Also see the section on practical coping strategies

sIBM will have a major impact on a patient's lifestyle, primarily, in mobility issues and issues involving daily life functions. For example, many patients have difficulty with functions in the bathroom such as getting up off the toilet and conducting personal hygiene. Bathing and showering become major tasks and are very dangerous given the risk of falling. Eventually, assistance will be required to perform these basic functions along with adaptive devices (for example, overhead track in the bedroom and bathroom).

Activities in the bedroom are also affected. It becomes difficult to roll one self over in bed and being in one position too long can cause bed sores. Getting in and out of bed can be an issue.

For men, although erections are not affected, it becomes impossible to support oneself while making love in the missionary position (man on top).

As the disease progresses, patients may have difficulty feeding themselves.

Activities in the kitchen must also be curtailed as, for example, it becomes impossible to open a can or to lift a full saucepan. As mentioned above, any activity involving the fingers or lifting objects becomes a challenge.

As our activity level decreases it becomes more and more important to eat a balanced diet and to reduce our overall intake of food (because fewer calories are required as we move less). The less weight we carry, the less our muscles will have to lift and also the better to prevent cardiac trouble or diabetes.

Driving becomes challenging as it is often difficult to lift the foot from the accelerator onto the brake pedal (obviously a very dangerous scenario). Steering is also affected as it becomes difficult, even with power steering, to turn the wheel a full rotation. Installation of hand controls can be effective in the short term but eventually these also become impractical. These factors often lead to having to eventually give up driving. Finally, getting in and out of the car becomes difficult and eventually impossible. As the illness progresses, many patients who can no longer walk and who must resort to electric wheelchairs, acquire wheelchair vans for transportation. (Although many patients buy inexpensive scooters this is not recommended as we will be spending essentially all of our waking hours in the chair and this makes it important to have a custom-made seat that is correctly sized for our body. These specialized seats are generally only available on electric wheelchairs. In addition, electric wheelchairs have many other advantages over scooters).

As mentioned above, while sIBM will affect one's lifestyle it should not shorten one's life span. In coping with this illness I have suggested that people need to be flexible and positive in dealing with their symptoms. It is especially important to realize when you need help, to ask for help and to accept help and this may involve eventually having a full-time caregiver. This illness can be very stressful and challenging especially on the spouses and great care is suggested to prevent caregiver burnout occurring in the spouse or other primary caregiver. These changes can be very difficult to accept, especially for older males, but they are directly related to the success in dealing with this frustrating disease. I have found it important that as I have had to give up things, for example, my job, driving, some of my hobbies -- I have been able to replace these activities with other positive ways to still make a contribution to life and to remain engaged in life -- this webpage is an example. Our challenge is to derive as much quality of life as possible while managing these frustrating symptoms. It's my belief that we should always be positive in remembering that this disease does not affect the heart or brain, thus we should be thankful that it is not worse than it is.

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1-1 C). The course, incidence and prevalence of sIBM.

Because IBM is so variable, we don't know two critical things about sIBM:

What is the course of sIBM once it starts?

How is the disorder going to affect people who get it? We need to know this to see if a treatment is effective. For example, if we KNEW that sIBM causes a 10% decline in strength every year, and we treat it and we can see that this decline goes down to 5% a year, then we can infer that the treatment works, at least to some extent. But, we don't know the course of the illness to begin with and this makes it hard to judge how effective treatments are. A treatment may not increase strength but may slow down the progression, again this is hard to judge when we know little about the course of the disorder. Researchers stress that the presentation of IBM (the symptoms that are observed) are quite variable in different people and as well, the rate of progression appears to be quite variable as well. In addition, it is well known that the disorder comes on at different ages, likely ranging from onset in the late 30s and up (20% of cases report symptoms in their 40s and the disease probably has been going on for some time before symptoms are noticed). The hereditary form usually strikes at an earlier age.

Rate of decline: How fast will it progress? There is no "textbook" figure to go by. This is also a bit hard to see as atrophy of the muscle (shrinkage) does not affect perceived strength at first. I have read that an atrophy of about 50% is needed before a person notices that a muscle feels weak. There is no doubt that the disease is affecting muscles for some time (likely years) before a person notices symptoms and goes to a doctor and the diagnosis is made. By the time of the diagnosis, a great deal of muscle has already been damaged. From the time of diagnosis, the rule of thumb seems to be that a patient "will require an assistive device, such as a cane, walker or wheelchair, within several years of onset." (Dalakas, 2006 )

• Dalakas, 2006 notes that the older the age of onset, the more rapidly progressive is the course.
• Is the decline steady or does it get steeper with time?
• Are different people affected differently and if so, why? This is a real problem for research.
• Are different people affected differently based upon their age when they get the disorder?
• Also, exactly when do we get it? How long do we have it before we notice weakness (it is possible we have it all of our lives)?

What is the incidence and prevalence of sIBM?: How common is it?

sIBM is a rare disease but the true incidence of sIBM is a bit unclear and not much research exists on the number of cases or of the ages when people are first diagnosed. In the past, studies have suggested that it is diagnosed in only about 5 people per million population, although some doctors have said they feel the actual numbers are much higher.

The most recent research, done in Australia, indicates that the incidence of IBM varies and is different in different populations and different ethnic groups. The authors found that the current prevalence was 14.9 per million in the overall population, with a prevalence of 51.3 per million population in people over 50 years of age. Needham et al, 2008.

Barohn (2006) said there was an annual incidence of 2 to 5 cases per 100,000 (or about 20 to 50 cases per million).* In other words, this implies that about 6000 cases per year would be diagnosed as having sIBM. It is more common in men (2 to 3 males to 1 female).

* Barohn, R J. MD; Herbelin, L BS; Kissel, J T. MD; King, W PT; McVey, A L. MD; Saperstein, D S. MD; Mendell, J R. MD. Pilot trial of etanercept in the treatment of inclusion-body myositis. Neurology Volume 66(2) Supplement 1, pg. S123-S124, January 24, 2006.

Dalakas, 2006 said: 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.

It is very likely that many people have sIBM who never get diagnosed (and many people are likely diagnosed and treated as PM cases). Also, there may be many people out there with mild cases who get weaker as they age and say "I'm just getting older." So, a lot of people may die having sIBM and never realize it: they never seek medical help. Biopsy is very invasive and expensive, so it is not practical to do in every case. But if we did more, perhaps we would find that sIBM is more common than we think.

sIBM is considered a rare disorder. For comparison, about 1 in 500 people has Multiple Sclerosis (MS). "So, if it is so rare, how can Dalakas call it the most common muscle disease after age 50?" In my opinion, this is a bit misleading because by age 50, all of the other muscle diseases that a person can get have already shown up, so I think sIBM is one of the only muscles diseases left that can show up after 50 (and remember that about 20% of cases show symptoms before the age of 50 as well). Still, people who are severely enough affected to go to the doctor and to get diagnosed with sIBM may only be the tip of a larger iceberg. As it is, our low numbers create a problem: there are not enough people to do good studies on.

The hereditary inclusion body myopathy forms are extremely rare, some forms with as few as 15 cases, others with a few hundred cases confirmed worldwide.

Incidence is a measure of how many people are diagnosed with an illness per 100,000 (or per some other index) over a period of time (usually one year). Thus, incidence is a measure of the risk of developing some new condition within a specified period of time. For example, if a population initially contains 1,000 non-diseased persons and 28 develop a condition over two years of observation, the incidence proportion is 28 cases per 1,000 persons, i.e. 2.8%. The prevalence of a disease is defined as the total number of cases of the disease in the population at a given time, or the total number of cases in the population, divided by the number of individuals in the population. It is used as an estimate of how common a condition is within a population over a certain period of time. From: Incidence (epidemiology). (2008, December 17). Wikipedia, The Free Encyclopedia. Retrieved 03:13, December 29, 2008

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1-1 D). Fact sheets.

An sIBM fact sheet from: The Muscular Dystrophy Campaign (UK).

An sIBM fact sheet from the Rehabilitation Research and Training Center in Neuromuscular Diseases (RRTC/NMD) at the University of California, Davis: Direct link as of 01/2006: http://disability.ucdavis.edu/

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1-1 E). Genetics.

Sporadic inclusion bodies myositis is not an inherited disorder and is not passed on to children. The latest view is that sIBM is a disorder influenced by a number of genes (a polygenetic disorder) that is predisposed by the interaction of a number of genes with each other. Based on our understanding of other polygenetic disorders, it is likely that such a predisposition would also interact with environmental variables further increasing or decreasing the probability of an individual developing the disorder. Such variables may be age (young cells decrease the probability, older cells increase the probability) or some exposure to sort of acquired virus. There are very rare forms of IBM (hereditary inclusion body myopathy) that are related to specific genetic mutations and that are passed on to children, however, there has not been a particular gene defect linked to sporadic inclusion body myositis.

When we think about genetic diseases, we generally think of mutations occurring in a particular gene that causes some sort of illness. No such genetic defect has been detected and directly linked to sporadic inclusion body myositis. It's important to realize that different individuals and different groups of people show slightly different combinations of genes. Groups of people from different ethnic backgrounds and from different geographical locations will share distinctive genetic ancestry that differs from groups of people from different areas and different backgrounds. Research on the genetics of sporadic inclusion body myositis has uncovered a group of genes that are present in about 70% of the cases tested. This cluster of genes has also been associated with higher incidences of several other autoimmune disorders such as rheumatoid arthritis. This group of genes is most common in Caucasian people with Northwestern European ancestry. A couple of other signs point to a genetic predisposition in sporadic IBM. One sign is that in a few rare cases, sIBM is seen in brothers and sisters within the same generation. This is called familial IBM and is mentioned below. Finally, the fact that there are several forms that are definitely genetic (although exceedingly rare) that are similar to the sporadic type are an indication that there likely is some sort of genetic interaction somewhere in the sporadic form as well. Research on other diseases has indicated that genetic predispositions often interact with environmental variables. In summary, there may be a pattern of genes involved in creating a susceptibility to getting sIBM but this particular combination of different genes would not likely be passed on to children, therefore, while sIBM may be predisposed by a person's genetic makeup, this form is not considered an inherited disease per se.

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1-1 F). Some basic terminology and relevant abbreviations. Ankle-foot orthosis a brace, usually plastic, worn on the lower leg and foot to support the ankle, hold the foot and ankle in the correct position, and correct foot drop. Also known as a foot-drop brace. aspiration = having food "go down the wrong way" and enter the lungs usually causing pneumonia derm = skin dermatomyositis = a widespread inflammation of the body's muscles with a major skin component (a rash) dysphagia = difficulty in swallowing. In IBM dysphagia is caused by weakness in the muscles in the throat familial: a disease where more than one case occurs in family members in the same generation (more than would normally be statistically expected) but not passed from generation to generation. hereditary [inherited] = genetic cause: passed on from generation to generation idiopathic: a term indicating of unknown cause inclusion = a bundle or clump. An inclusion body is an abnormal structure in a cell nucleus or cytoplasm having characteristic properties when seen under the microscope (using different stains to highlight different things in the tissue sample). Inclusion bodies are a characteristic of sIBM. Knee-Ankle-Foot Orthosis A KAFO is a long-leg orthosis that spans the knee, the ankle, and the foot in an effort to stabilize the joints and assist the muscles of the leg. Myo = muscle myositis = inflammation of the muscle myopathy = pathology (destruction / disease) of muscle "pathy" = disease / death / destruction / severe illness poly = many, multiple "sitis" = inflammation of something sporadic [spontaneous] = unpredictable, it just shows up, cause unknown vacuole = a hole. A vacuole is small cavity in the cytoplasm of a cell, bound by a single membrane and containing water, food, or metabolic waste. Some diseases are characterized by abnormal vacuolization of certain tissues; too many and/or too big (e.g., Alzheimer's has abnormal vacuoles in the brain, as well as various muscle diseases including sIBM). In, addition, the vacuoles often contain abnormal chemicals and other things that shouldn't be there. Relevant abbreviations: - AβPP amyloid-β precursor protein - AD Alzheimer Disease - AD-IBM Hereditary autosomal dominant inclusion-body myopathy; autosomal dominant inclusion body myopathy - ADDLs Aβ-Derived Diffusible ligands - AFO Ankle-foot orthosis - AH ancestral haplotype - αB-C αB-crystallin - α-syn α-Synuclein - AP alkaline phosphatase - APC antigen-presenting cell - APP amyloid precursor protein - ApoE apolipoprotein E - AR-hIBM Autosomal recessive Hereditary Inclusion Body Myopathy - CMA Chaperone-mediated autophagy - COX cytochrome-c-oxidase - CTL chymotrypsin-like - DCs dendritic cells - DM dermatomyositis - DMRV distal myopathy with rimmed vacuoles (Nonaka) - ER endoplasmic reticulum - ERK extracellular signal regulated kinase - fIBM familial cases of inclusion-body myositis - hIBM hereditary inclusion body myopathy - human leukocyte antigen (HLA) - IBMPFD IBM associated with Paget's disease and frontotemporal dementia - IBM3 (previously known as AD myopathy with congenital joint contractures, ophthalmoplegia and rimmed vacuoles). - IIMs Idiopathic inflammatory myopathies - IBM2 Inclusion Body Myopathy 2 - KAFO Knee-Ankle-Foot Orthosis - MHC major histocompatibility complex - MSTN myostatin - OMIM Online Mendelian Inheritance in Man - PGPH Peptidyl-Glutamyl Peptide-Hydrolytic - PHFs paired helical filaments - PM polymyositis - PrPC prion protein [the normal or cellular type] - p-tau phosphorylated tau protein - QSM quadriceps-sparing myopathy (Quadriceps-sparing Inclusion Body Myopathy) - RRF ragged-red fibers - s-IBM sporadic inclusion body myositis - SMN survival motor neuron - TCR T-cell receptor - TL trypsin-like - VCP valosin-containing protein - UPS ubiquitin-proteasome system

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1-2). The current classification of IBM.

1-2A). Classification of the Myositis Forms

Overview:
- Sporadic (or spontaneous) inclusion body myositis (sIBM)
- Familial inclusion body myositis (fIBM)

a). Sporadic (or spontaneous) inclusion body myositis (sIBM):

• This is the form most commonly seen, if you have been diagnosed with "IBM," this is likely what they are referring to (properly called sIBM to indicate the sporadic classification, although many times the "s" is left off).
• Inflammation is the prominent feature along with several other characteristic features, therefore it is classified as a muscle myositis (called a myositis because its prominent feature is muscle inflammation (myo -- sitis: myo means muscle and "sitis" means inflammation).
• Sporadic and spontaneous are terms that mean that it just "shows up" no cause is known. Some doctors believe that further research may reveal that the so-called "sporadic" forms of inclusion body myositis may be related to the same types of genetic defects seen in some of the known hereditary forms.

Inclusion Body Myositis is characterized by three major changes in the muscle cells:

• Inflammation.
• The presence of vacuoles ("holes") within the muscle fibres.
• Inclusion bodies ("plates" or plaques of abnormal protein and clusters of tangled filaments made out of abnormal protein strands) within the vacuoles. There are also many other abnormal changes seen within the muscle cells.

b). Familial inclusion body myositis (fIBM):

• Familial (inflammatory) inclusion body myositis (fIBM). Looks identical to sIBM, however, in familial IBM, more than one case occurs in family members in the same generation. This condition is different from hereditary inclusion body myopathy (hIBM) but the familial form is often confused with hereditary inclusion body myopathy in the literature.
  In this context, familial refers to the fact that it shows up in the same generation of a family more than would normally be expected but it is apparently not passed from generation to generation.
• Very rare.
• "The familial occurrence of such a rare disease highlights the importance of genetic predisposition in the etiology and pathogenesis of sIBM." Needham M, Mastaglia FL, Garlepp MJ. (2007).

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1-2B). Classification of the Myopathy (Inherited) Forms:

a). Overview:

• Familial IBM is associated with the typical features that are seen in sIBM, but occurs in siblings in the same generation. The familial occurrence of such a rare disease highlights the importance of genetic predisposition in the etiology and pathogenesis of sIBM. see Needham et al (2007) .
• One category of IBM illnesses, the hereditary inclusion-body myopathies (hIBM) are linked to specific genetic defects and are inherited; they are passed down from generation to generation. To date there is no indication that the genes responsible for these conditions are involved in sIBM.
• hereditary inclusion body myopathy (hIBM)
  • Different characteristics than seen in sIBM (examples: little inflammation, strikes people at a younger age [some in their twenties]).
  • A muscle myopathy (does not display primary lymphocytic inflammation, therefore researchers called it a myopathy, not a myositis) [myo = muscle, pathy = disease].
  • A heterogeneous group of disorders (there are a number of subtypes, they are not all the same), they are also clinically heterogeneous (they present with different symptoms), several different types have recently been described under various names (see Rodolico 2005, below).
  • extremely rare, some forms with as few as 15 cases, others with a few hundred cases confirmed worldwide.
  • Diagnostic criteria of h-IBM have not yet been widely established.
  • Each form is thought to be linked to a specific genetic mutation (some have been discovered but not all).
  • Passed on in families from generation to generation.
  • Hereditary inclusion body myopathies comprise both autosomal recessive and autosomal dominant modes of inheritance.
  • Autosomal recessive forms
    • Hereditary Inclusion Body Myopathy (hIBM). Alternative names: Inclusion Body Myopathy 2 (IBM2); Autosomal recessive Inclusion Body Myopathy AR-hIBM; Quadriceps-sparing Inclusion Body Myopathy (QSM); Nonaka distal myopathy with rimmed vacuoles; Distal myopathy with rimmed vacuoles (DMRV)
    • For more information on hIBM-2, see: Hereditary Inclusion Body Myopathy
  • Autosomal dominant forms
    • Hereditary autosomal dominant inclusion-body myopathy; autosomal dominant inclusion body myopathy (AD-IBM)
    • IBM3 (previously known as AD myopathy with congenital joint contractures, ophthalmoplegia and rimmed vacuoles).
    • IBM associated with Paget's disease and frontotemporal dementia (IBMPFD)

b). Types currently linked to defects on specific chromosomes:

• Chromosome 9: Types of hereditary inclusion body myopathy currently linked to the GNE gene on chromosome 9 located at 9p12-p11.
  • An autosomal dominant form where the quadriceps are one of the first muscles to become weak.
  • An autosomal recessive form (IBM2), common among people of Middle Eastern and Jewish heritage. This form mainly affects leg muscles, but with an unusual distribution that spares the quadriceps; the quadriceps are among the last muscles to become weak (quadriceps-sparing myopathy QSM).
  • Nonaka distal myopathy with rimmed vacuoles, essentially a form of IBM2.
• Chromosome 9: IBMPFD is linked to a slightly different gene on chromosome 9, located at 9p13-p12.
• Chromosome 17: Inclusion body myopathy-3 (IBM3) is linked to mutations in a gene encoding myosin heavy chain II proteins on chromosome 17 (located at 17p13.1).
• It would not be a surprise if more types of inclusion body myopathy linked to other genes were identified in the future.

c). Details of the major subtypes of inherited forms as currently described:

• I). Autosomal recessive forms: The mutation is inherited in a recessive fashion.
  • i). Hereditary Inclusion Body Myopathy (hIBM). Alternative names: Inclusion Body Myopathy 2 (IBM2); Autosomal recessive Inclusion Body Myopathy AR-hIBM; Quadriceps-sparing Inclusion Body Myopathy (QSM); Nonaka distal myopathy with rimmed vacuoles; Distal myopathy with rimmed vacuoles (DMRV).
    • See: OMIM # 600737.
    • Onset: 2nd to 4th decade.
    • Characterized by adult onset, slowly progressive distal and proximal weakness and a typical muscle pathology including rimmed vacuoles and filamentous inclusions.
    • The autosomal recessive form described in Jews of Persian (Iranian) descent is the hIBM prototype. High-risk groups include Jews of Persian descent, among whom one out of 10 to 20 people is believed to carry the mutated hIBM gene, and Iranians, where it is estimated that 1 in 500 is affected. These mutations also have been identified in individuals from eastern India, the Bahamas, and the state of Georgia in the United States.
    • To date, more than 40 different mutations in the GNE gene have been reported to cause AR hIBM.
    • This myopathy affects mainly leg muscles, but with an unusual distribution of weakness that spares the quadriceps.
    • This particular pattern of weakness distribution, termed quadriceps-sparing myopathy (QSM), was later found in Jews originating from other Middle Eastern countries as well as in non-Jews.
    • CK elevation: Mild elevation, 2x to 5x
    • Associated with mutations in a gene on chromosome number 9 (location: 9p12-11). The mutations affect an enzyme that plays a crucial role in the synthesis of sialic acid, a vital carbohydrate ingredient in the formation and functioning of numerous proteins. Scientists hypothesize that lack of sialic acid leads to accumulation of defective proteins in muscle cells, thus causing muscle degeneration. The gene is called the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene, the enzyme is called UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase. See: OMIM 603824
    • The mutation can be sporadic (the mutation just occurs in an individual) or Recessive (the mutation is inherited in a recessive fashion).
    • Mutations associated with deleterious effects of too much sialic acid (sialuria) are located in the epimerase domain, and those associated with IBM2 (deficiency of sialic acid) are in the epimerase or the kinase domain or both.
    • Nonaka (or Nonaka distal myopathy with rimmed vacuoles):
      • In 1981, Dr. Nonaka and his team described a form of muscular dystrophy with predilection for distal muscles, especially the anterior tibial muscles, and onset in early adulthood. The EMG demonstrated a myopathic pattern and CPK was mildly elevated. Rapid clinical progression was observed. Nonaka thought the disorder in their families was autosomal recessive and stated that the disorder appears to be common in Japan. The mutations observed in Nonaka myopathy are located in the sugar kinase domain of the GNE gene. This is an allelic disorder [essentially the same thing genetically] to Autosomal recessive inclusion body myopathy type 2 (IBM2) with a similar phenotype [the same symptoms]. The clinical phenotypes are very similar in the two groups of patients with presentation between 10 and 40 years of age with anterior compartment weakness leading to the development of a bilateral foot drop. The posterior calf muscles are affected at a later stage as well as more proximal muscle groups such as the iliopsoas, hamstrings, gluteal muscles and thigh abductors, but with a remarkable sparing of the quadriceps femoris muscles even in the late stages of the disease. Weakness of proximal upper limb muscles and later distal muscles of the forearm and hand as well as the neck flexors also occurs.
      • See: OMIM # 605820
      • Reference: Nonaka, I.; Sunohara, N.; Ishiura, S.; Satoyoshi, E. Familial distal myopathy with rimmed vacuole and lamellar (myeloid) body formation. J. Neurol. Sci. 51: 141-155, 1981.
    • DMRV is known to be the same disease as hereditary inclusion-body myopathy (HIBM), which was originally reported as quadriceps-sparing myopathy. DMRV/HIBM is caused by mutations in the GNE gene encoding UDP-N-acetylglucosamine 2 epimerase/ N-acetylmannosamine kinase, a bifunctional enzyme in the sialic acid synthetic pathway. Genetically confirmed cases of DMRV/HIBM have been found in Iranian Jews, Japanese, Koreans, Chinese, Americans, and Europeans. However, no case has been reported from Southeastern Asian countries, so far as we are aware. Herein, we report four unrelated Thai patients with DMRV confirmed both clinicopathologically and genetically. Reference: TEERIN LIEWLUCK, et al, MUTATION ANALYSIS OF THE GNE GENE IN DISTAL MYOPATHY WITH RIMMED VACUOLES (DMRV) PATIENTS IN THAILAND, Muscle Nerve 34: 775-778, 2006.
    • "To date, more than 40 different mutations in the GNE gene have been reported to cause AR hIBM. Interestingly, homozygous missense GNE mutations have been reported in some clinically unaffected individuals, indicating that other factors play a role in the pathogenesis of disease. Such factors, which are not yet elucidated, seem to be important in the clinical expression of disease in all patients; although the gene defect is present from conception, it may not result in clinically manifest disease until the third or fourth decade. Mutations in GNE have not been found in cases of sIBM, but the possibility that other variations in the gene may influence susceptibility to sIBM has not been investigated." From: Needham et al (2007).
    • For more information on hIBM-2, see: Hereditary Inclusion Body Myopathy

• II). Autosomal dominant forms: The mutation is inherited in a dominant fashion. "There are several forms of autosomal dominant inclusion body myopathy (AD-IBM) having different clinical presentations and in most of them, the genetic defects are not known" (Rodolico, 2005).
  • i). Hereditary Inclusion Body Myopathy: also called Hereditary autosomal dominant inclusion-body myopathy; autosomal dominant inclusion body myopathy (AD-IBM):
    • Onset: Adult; 20 to 40 years
    • Distal: Foot Dorsiflexion
    • Proximal: After disease progression
    • CNS involvement occurs in some families
    • Serum CK: Normal or Mildly increased
    • An autosomal dominant disease (only need to inherit one faulty gene from one parent).
    • See: http://www.neuro.wustl.edu/neuromuscular/musdist/distal.html#hibmd
  • - Needham et al (2007) lists IBM1 under this category, see: OMIM 601419.
  • - Most recent reference on autosomal dominant inclusion-body myopathy: Clinical and muscle magnetic resonance imaging study of an Italian family with autosomal dominant inclusion body myopathy not linked to known genetic loci.
    Rodolico C, Toscano A, Patitucci A, Muglia M, Gaeta M, D'Arrigo G, Migliorato A, Messina S, Quattrone A, Messina C, Vita G.
    Department of Neurosciences, Psychiatry and Anaesthesiology, University of Messina, A.O.U. "G. Martino", Via C. Valeria, I-98125, Messina, Italy, crodolico@unime.it.
    December 2005, Neurol Sci. 2005 Dec;26(5): 303-9.
    Abstract: The objective was to report a clinical, pathological and muscle magnetic resonance (MR) study of an Italian family with an autosomal dominant inclusion body myopathy (AD-IBM). Eight subjects (age range 20 to 56 years; 5 females and 3 males) belonging to four generations were studied. Onset of disturbances (distal weakness at lower limbs) ranged from 20 to 28 years. CK levels were increased to five times. Only in an early stage oedema of involved muscles has been demonstrated by muscle MR. Quadriceps femoris was characteristically spared; in the last phases a mild involvement of the vasti became evident with persistent sparing of the rectus femori. Rimmed vacuoles and hyperphosphorylated tau filaments were evident at muscle biopsy. Linkage analysis excluded the association of the disease to chromosome loci 14q11, 17p13.1, 2p13, 19p13. [In an early phase of the disease quadriceps femoris was characteristically spared; in the last phases a mild involvement of the vasti became evident with persistent sparing of rectus femori.] The study suggests that quadriceps sparing is a characteristic feature also of AD-IBM. This finding could represent a muscle-image hallmark helpful in diagnosis of autosomal dominant muscular disorders.
  • ii). Hereditary inclusion body myopathy with Joint Contractures & Ophthalmoplegia, inclusion body myopathy-3 (IBM3). OMIM: #605637 The mutation is on Chromosome # 17 in location 17p13.1.
    • An autosomal dominant disease (only need to inherit one faulty gene from one parent) that results from mutations in the gene encoding myosin heavy chain IIa (MYHC2A, or MYH2). Myosin heavy chains (MYHCs) are ubiquitous actin-based motor proteins that convert the chemical energy derived from hydrolysis of ATP into mechanical force that drives diverse motile processes, including cytokinesis, vesicular transport, and cellular locomotion, in eukaryotic cells. This form is very rare and currently has been isolated in one Swedish family.
  • iii). Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD) OMIM #167320
    • Various other names:
      • MUSCULAR DYSTROPHY, LIMB-GIRDLE, WITH PAGET DISEASE OF BONE
      • PAGETOID AMYOTROPHIC LATERAL SCLEROSIS
      • PAGETOID NEUROSKELETAL SYNDROME
      • LOWER MOTOR NEURON DEGENERATION WITH PAGET-LIKE BONE DISEASE
    • A rare, complex and ultimately lethal disorder caused by an autosomal dominant genetic defect on Chromosome # 9 in location 9p13.3-p12, that leads to production of a mutant (diseased) valosin-containing protein (VCP). For the best overview of these complex variants, see: http://www.neuro.wustl.edu/neuromuscular/musdist/distal.html

[Based upon the classification of the Neuromuscular Disease Center, Washington University, St. Louis, MO., USA]

Note: OMIM is a catalog of human genes and genetic disorders run by the National Center for Biotechnology Information. I have provided the numbers for the OMIM descriptions (where available) for these disorders, click on them for more information.

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1-2C). Idiopathic inflammatory myositis or idiopathic inflammatory myopathies.

• Inclusion Body Myositis and Inclusion Body Myopathy are often classified as belonging to the idiopathic inflammatory myositis (IIM) diseases, or sometimes referred to as just inflammatory myositis (IM).
• Idiopathic means that they don't know what causes it.
• Dalakas sometimes refers to these diseases as autoimmune myopathies.
• There are two other major types of IIMs, dermatomyositis (DM) and polymyositis (PM).
• There are some similarities between polymyositis and IBM (and some big differences) but dermatomyositis appears to be a distinctly different disease.
• For some reason, polymyositis and especially dermatomyositis, but not IBM, are also associated with the development of malignancy (cancer), see: Curr Opin Rheumatol 18:620-624.
• These idiopathic inflammatory myositis (IIM) diseases fall under the wider umbrella of muscular dystrophy diseases:
  • Muscular dystrophy
    • idiopathic inflammatory myositis (IIM) diseases
      • dermatomyositis
      • polymyositis
      • sporadic IBM and the other inherited types; hIBM, IBM3, etc.

Other major diseases under the muscular dystrophy (MD) umbrella include myotonic dystrophy, Duchenne MD, Becker MD, Spinal Muscular Atrophy (SMA) as well as about 120 other diseases so far identified, some with many different subtypes. IBM is unique in its presentation among the muscular dystrophies.

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1-2D). Sporadic inclusion body myositis versus Polymyositis.

Polymyositis (PM) shows some features in common with IBM, and IBM is often first mistakenly diagnosed as polymyositis. It appears that in polymyositis there is the same sort of immune reaction against muscles that occurs in sIBM. In polymyositis, muscle cells display "flags" (MHC class I antigens) on their surfaces alerting the immune system that they are infected or damaged and the immune system attacks (with CD8+ cells) and kills them.

Patterns of inflammation in polymyositis and s-IBM are identical but different from patterns found in other muscular dystrophies that are known to exhibit inflammation (dermatomyositis). Polymyositis tends to come on over weeks or months as opposed to the onset of IBM which is usually over months or years. A major difference is that in PM there is no muscle fiber degeneration noted - there are no inclusions or abnormal proteins seen and PM generally responds well to therapy whereas sIBM does not. Cases of PM that do not respond to treatment are likely actually misdiagnosed IBM. IBM tends to strike a different population (generally of older men) compared to PM. In conclusion, s-IBM and polymyositis appear to share a primary immune process with antigen-driven T cells invading non-vacuolated muscle fibres, but sIBM also appears to involve a secondary degenerative process in which abnormal proteins are involved in vacuolar degeneration of the muscle fibres.

It appears that dermatomyositis is a different disease altogether, although it is still classified along with PM and IBM as an inflammatory myositis.

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1-2E).Terms and types of genetic disease transmission / acquisition that we need to differentiate: There are several aspects we need to be clear about: spontaneous disorders inherited genetic disorders. spontaneous genetic disorders familial disorders congenital disorders multigenic, multifactorial disorders a). Spontaneous Disorders. The term spontaneous is used to refer to IBM cases (sIBM) that simply arise in people. In these cases, there is usually no family history, the individual is the only person with the disorder in the family and there is no reason to suspect that it has been inherited. At this point, no specific mutation is linked to sIBM and therefore, it is also assumed that the sIBM will not be directly passed on to offspring. b). Inherited Genetic Disorders. When we talk about inherited diseases, we are usually talking about single gene diseases that are are usually linked to a specific genetic mutation. About 4000 such diseases have been identified. These disorders "run in families" and are passed on from a parent to an offspring via sperm or egg cells that carry a mutation. Usually, the individual inherits the same mutation that the parent has (although in some conditions the mutations can change slightly and can become more or less serious over generations). The different types of hIBM fall under the category of inherited genetic disorders. An individual with hIBM can pass it on to his or her offspring. hIBM may show dominant or recessive inheritance, depending upon the type involved. c). Spontaneous Genetic Disorders. In spontaneous genetic disease, the egg and sperm cells inherited from mom and dad start out as normal, but after conception, as the cells replicate, a defect in the gene code occurs (a mutation) and causes a disease. This type of new mutation may occur in a sperm or egg cell or it may occur in a body (somatic) cell. If it occurs in a somatic cell, it may well cause disease in the individual (usually cancer) but it will not be passed on to future offspring. If the new mutation occurs in an egg or sperm cell, it may cause a disorder in the individual and may also be passed on to offspring (this is how all genetic diseases originally start out). The individual with the new (spontaneous) egg or sperm cell mutation is the starting point for the inherited disorder in his or her family tree. In these cases, no prior family history will be present as the mutation just occurred in this generation. d). Familial disease refers to a disease occurring in more members of a family in a single generation than would be expected by chance alone. Not inherited. Familial often is (wrongly) used interchangeably with hereditary or inherited. On this page, familial means that more than one case of sIBM occurs in family members in the same generation, but this does not mean that the disease is inherited or hereditary (it is not passed on from one generation to the next, from parent to child). e). Congenital diseases: Strictly speaking these are conditions present at birth - symptoms are present at birth. Congenital anomalies may be inherited or sporadic, isolated or multiple, apparent or hidden, gross or microscopic. IBM illnesses are not congenital as they do not manifest symptoms until later in life. f). Multigenic, Multifactorial Disorders (diseases with complex segregation patterns): Most common diseases (cancer, heart disease, etc.) are not related to a single gene or to a single mutation and do not conform to the simple, single genetic inheritance picture described above (point 2). They cannot be easily classified as dominant or recessive (they have complex segregation patterns). They are called multifactorial disorders (also called "complex diseases"). There is usually a pattern of genes present which, by themselves, are neither necessary nor sufficient to cause the disease. These genes interact with other genes and with environmental factors to predispose the disease. An example are autoimmune diseases. sIBM likely falls under the category of a multigenic, multifactorial disorder. Genetic Inheritance Background: There are two main classes and four types of single-gene genetic diseases: A). Recessive diseases: These are diseases where two copies of a defective gene must be inherited, one from each parent to get the disease. Inheriting this gene error from only one parent usually causes the person to be a "carrier" of the disease, able to pass it on to offspring, but usually without any sign of symptoms. (hIBM type 2) B). Dominant diseases: These genetic diseases only require a single copy of the defective gene to be inherited from either mom or dad. The bad gene from one parent dominates the corresponding good gene from the other parent. There is no such thing as a "carrier" of a dominant disease because everyone who has the genetic error gets the disease. (hIBM 1, hIBM 3 and IBMPFD) With this in mind, there are actually four major types of genetic diseases with different inheritance patterns: 1). Autosomal recessive genetic diseases: Disease occurs when both copies of a mutated gene on chromosome 1 to 22 are inherited from both parents. The two bad copies combine to cause the disorder. (hIBM type 2) 2). Autosomal dominant genetic diseases: Disease occurs when a single mutated copy of a gene on chromosome 1 to 22 is inherited from either parent. The bad copy dominates the other good copy to cause the disorder. (hIBM 1, hIBM 3 and IBMPFD) 3). X-linked recessive genetic diseases: A single gene error on the X chromosome causes disease in men (who have only one copy of X) but usually not in women (who have two copies of X, usually in these cases, one mutated and one healthy, the healthy one is usually enough to compensate). (Hemophilia and Duchenne muscular dystrophy). 4). X-linked dominant genetic diseases: A single gene error on the X chromosome will cause the disease in both men and women. Men have only one copy of X, so get the disorder. In women (who are XX) the bad copy dominates the good copy and they get the disorder. X-linked dominant diseases are much rarer than X-linked recessive diseases. (Y-linked diseases are essentially unknown.)

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1-3). Diagnosis.

1-3 A). How is sIBM diagnosed?

a). Clinical Signs

Clinical signs are the symptoms the doctor can see when he or she examines you. The first common clinical signs of sIBM are falling down and tripping and weakness in the finger flexors: the muscles involved in grip. Doctors look for the characteristic patterns of weakness and wasting (shrinkage) described above, in particular, in the quadriceps and the finger flexor muscles.

b). Tests Commonly Done

• A blood test of Creatine kinase (CK) (also known as "phosphocreatine kinase," or CPK). This is an enzyme in the blood, elevated levels indicate that muscle damage has occurred, or is occurring. Typically, in sIBM, CK values are, at most, about 10 times normal levels although this may vary and normal CK values may be seen.
• Electromyography (EMG): Electrical studies of the muscle done with a electromyograph will display abnormalities. This machine uses thin needles (similar to acupuncture needles) that are inserted into the muscle and that record the muscles' electrical activity on a computer. This test is usually done in conjunction with a nerve conduction study (NCS), a test that looks at the function of the nerves.
• Muscle Biopsy: The best test for IBM is a muscle biopsy (MBx).

       Important types of changes in the structure of muscle cells are characteristic of sIBM and often appear in a biopsy:

1. Inflammation is seen in the muscle: inflammatory cells are seen invading the muscle cells.
2. Degenerative changes in the muscle cell and protein accumulation

• Vacuoles ("holes") appear in the muscle fibers ("vacuolar degeneration");
• Inclusions ("clumps" of material) are found inside the muscle fibers, these are associated with the intracellular (inside the cell) accumulation and aggregation of several abnormal proteins;

3. There is evidence of mitochondrial involvement as evidenced by segmental deficiency of cytochrome c oxidase (COX-deficient fibers) and ragged-red fibers (RRF) see Needham et al (2007).

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1-3 B). Specific medical diagnostic criteria.

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1-3 C). Ambiguity of a Myositis Diagnosis:

• In general, neurological and muscular disorders can be a challenge to diagnose. Many muscle disorders begin slowly and weakness can be a symptom of a number of different disorders. Therefore, diagnosis of these disorders is a challenge and relies upon a combination of interpreting the symptoms present and the results of the tests done. In many cases, a diagnosis is tentative and needs to be monitored as symptoms develop and change as the disorder progresses. As mentioned elsewhere, the symptoms of sporadic IBM are quite similar to polymyositis and this diagnosis is often initially made and treatment initiated. Polymyositis will generally respond well to treatment confirming the diagnosis whereas if there is little or no response to treatment then the diagnosis should be reconsidered with spontaneous IBM in mind. At this point a biopsy would generally be recommended.
• Generally, a biopsy is needed to add more certainty to the clinical diagnosis. Even with a biopsy there can be still be some question about which illness is involved.
• Greenberg (2009) points out two common pitfalls in diagnosing IBM:
  • One, many patients are seen who present with "typical IBM-like pattern of weakness and perimyofiber distribution of inflammatory cells in biopsy specimens but lack rimmed vacuoles and congophilic myofiber deposits [5]. Many such patients are diagnosed with polymyositis even though they meet research criteria for possible [6] and probable IBM [7] but not 2004 proposed criteria for polymyositis [8]. In a recent retrospective study of the treatment responsiveness of 14 such "polymyositis/IBM" patients, none had no sustained improvement with immunosuppressive therapy, while 29% had stabilization; in comparison, all 24 patients with patterns of weakness typical of polymyositis showed improvement or stabilization with immunotherapy [9]. These studies support the importance of the pattern of weakness as the distinguishing feature predicting treatment response in patients with an inl ammatory myopathy. Whether patients with an IBM pattern of weakness, but without rimmed vacuoles and congophilic deposits, have a higher rate of disease stabilization with immunotherapy than patients with these pathologic features is an important question that likely would require a prospective treatment trial to answer."
  • Second, "Some case studies [of IBM patients] have reported a response to immunotherapies. These reports have consistently involved patients who do not have clinical features of IBM and were likely misdiagnosed based on biopsy criteria alone. A 2007 report of three patients with "biopsy-proven" IBM who responded well to cyclosporine or tacrolimus suffers from these limitations [10]; none of the patients had finger flexor, wrist flexor, or quadriceps atrophy or weakness, thus failing to meet research criteria for even possible [6] or probable IBM [7]. Two of the patients had very high serum creatine kinase levels, exceeding some research criteria limits [6]."

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1-3 D). The importance of a biopsy in sIBM:

• A muscle biopsy (MBx) is a very important test in diagnosing sIBM.
• See the MDA site for general information on muscle biopsies at: http://www.mdausa.org/publications/Quest/q74ss.html
• To start with, the pathologist looks at the muscle sample and notes any abnormalities that he or she can see. This is done under varying degrees of magnification and in various ways.
• To look for some of the abnormalities of sIBM, the biopsy has to be tested with different stains and enzymes. These tests can be very delicate, time consuming and expensive, however, the biopsy is only as good as the tests done on it. In many cases, very specialized laboratories are needed (the local hospital cannot do these complex tests).
• Even with a biopsy there can be some questions about what is needed to make the diagnosis of sIBM. For example, inclusion bodies are characteristic of sIBM, however, I believe that some doctors suggest that they are not always present. Vacuoles may also be present in some other types of muscular dystrophies. Inflammation also can be present in some forms of muscular dystrophy and of course, in PM and DM, so, inflammation is not an exclusive sign of sIBM. Also, Dr. Askanas has noted that inflammation can vary with the stage of the sIBM (more at the start, less at the end).
• In summary, even with a biopsy, diagnosis of sIBM is still open to some interpretation.

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1-4). Causes and abnormalities.

1-4 A). Synopsis of abnormalities seen in sIBM:

Inflammation:

• One primary feature of sIBM is inflammation of the muscle fibres (cells), representing a long term (chronic) activation of the body's immune response, apparently directed toward specific and consistent antigens ("targets") on the muscle cells that lead to inflammation and immune reactions that, in turn, lead to progressive muscle destruction and weakness. In sIBM muscle cells (myofibers) display "flags" (called MHC class I antigens) on their surfaces alerting the immune system that they are infected or damaged and the immune system attacks them with CD8+ CTLs. The CTLs secrete molecules that destroy the muscle cells.

Abnormal proteins:

• Also, in sIBM, there are many other abnormal protein changes within the muscle cells and ultimately, muscle fibre degeneration. These include several abnormal and presumably pathological proteins that collect and form inclusions ("lumps"), and strands of abnormal protein called "paired-helical filaments" (PHFs).
• At least 80 abnormal proteins have been described so far in sIBM samples (Greenberg, 2009). Greenberg (2009) notes that these results are based upon "immunohistochemical evidence alone without quantitation or sufficient exclusion of artifact."
• Askanas and Engel (2003) state that the "two major types of intracellular inclusions in s-IBM muscle contain either Abeta or phosphorylated tau" and that both types contain significant quantities of mutant ubiquitin protein (UBB+1) (Fratta, et al, 2004).
• Also see Oldfors and Lindberg (2005) for a recent synopsis of sIBM abnormalities.

How the different inflammation and cellular deterioration are related to each other (which come first, what causes what, etc.) is not well understood yet. Also, what abnormalities are responsible for just what symptoms is not well understood.

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1-4 B). Synopsis of possible causes of sIBM:

Overview:

• The basic cause of IBM has not been discovered although much is already known about the changes that take place in muscle affected by IBM.
• sIBM is likely a multifactoral disease, this means that it likely results from the interaction of a number of factors, both genetic and environmental. If just the "right" combination of factors occurs in a person, sIBM will develop.
• Needham et al (2007) conclude "The pathogenesis of sIBM is slowly being elucidated, and is likely to involve a complex interaction between environmental triggers (possibly viral) and genetic susceptibility."
• Currently, there are two main theories about how sIBM is caused:
  • 1). Some researchers advocate the theory that the inflammation / immune reaction, caused by an unknown trigger - likely an undiscovered virus or an autoimmune disorder (immune dysregulation), is the primary, proximal cause of sIBM and that the degeneration of muscle fibres and protein abnormalities are secondary features.
    • Despite the arguments "in favor of an adaptive immune response in s-IBM, a purely autoimmune hypothesis for s-IBM is untenable because of the disease's resistance to most immunotherapy." (Collins, Inclusion Body Myositis, eMedicine article from WebMD, Last Updated: May 15, 2006, Retrieved March 28, 2007 from http://www.emedicine.com/neuro/topic422.htm#section~introduction)
  • 2). Some researchers support the theory that sIBM is a degenerative disorder related to aging of the muscle fibres and that abnormal, potentially pathogenic protein accumulations in myofibers play a key causative role in s-IBM (apparently before the immune system comes into play). This theory emphasizes the abnormal intracellular accumulation of many proteins, protein aggregation and misfolding, proteosome inhibition, and endoplasmic reticulum (ER) stress.
    • This theory has emphasized the presence of a number of abnormal proteins such as beta-amyloid that are also seen in Alzheimer disease.
    • The interpretation of the evidence in support of the beta-amyloid-mediated theory has been questioned by Greenberg, for example, in a letter published in 2008 and replied to by Schmidt and Dalakas. For a recent review of the "limitations in the beta-amyloid-mediated theory of IBM myofiber injury," see Greenberg 2009.

sIBM as an inflammatory / immune system disease (also see 2-5, 2-9):

Update:

The molecular basis of IIMs in humans, as in many other autoimmune rheumatic diseases, is heterogeneous, involving several complex cellular components that probably contribute to differences in disease susceptibility, clinical and histopathological phenotype, and severity. Although this heterogeneity makes the study of the pathogenesis of IIMs extraordinarily complex, it might also provide distinct avenues for novel therapeutic interventions. Controlling the immune response is as complex as its launching. An essential feature of physiological immune response is its self-limitation, by which it is attenuated by several mechanisms. We have only just started to understand the orchestrated life of T lymphocytes, B lymphocytes, and DCs in IIMs, but there are still many unanswered questions about how this usually effective system can go awry and result in false immune-mediated reactions.

On the basis of detailed immunohistochemical studies on muscle biopsies, two major types of inflammatory infiltrate were observed: endomysial and perivascular/perimysial. In endomysial infiltrates there was a striking dominance of CD8+ T lymphocytes, which could even be the predominating infiltrating cell type, followed by macrophages and CD4+ T lymphocytes. These infiltrates often surrounded nonnecrotic fibers and sometimes seemed to invade the fibers. This observation suggests an immune reaction that targets muscle fibers. The perivascular infiltrates, in contrast, were dominated by CD4+ T lymphocytes and macrophages, and sometimes the presence of B lymphocytes suggested an immune reaction that targets microvessels. A role for B lymphocytes as well as one for CD4+ T lymphocytes in the pathogenesis of IIMs is supported by frequently detected autoantibodies in polymyositis and dermatomyositis but less often in inclusion-body myositis. These autoantibodies are both non-specific (frequently also being found in other autoimmune disease) and myositis specific [38,39]. A role for CD4+ T lymphocytes in the disease mechanism is further supported by the genetic association with HLA-DRB1*0301, DQA1*0501, and DQB1*0201, which was particularly seen for subgroups of patients with autoantibodies.

The endomysial infiltrates were reported to be characteristic features of polymyositis and inclusion-body myositis, whereas the perivascular infiltrates were associated with patients with dermatomyositis. However, there are cases with a less distinct localization of infiltrates or with combined endomysial and perivascular cellular infiltrates [3,6]. Moreover, in some cases the inflammatory cell infiltrates are diffusely spread in the tissue, whereas in other cases the infiltrates are very small or are not found at all. In addition, the perivascular changes may be seen in patients without a skin rash, whereas endomysial infiltrates are occasionally seen in cases with a skin rash.

Taken together, these results indicate that there may be two major pathways: one leading to cellular infiltrates with predominating endomysial localization [more often seen in patients with IBM and polymyositis], and another with a predominantly perivascular localization often with microvessel involvement and capillary loss. The latter is more often seen in patients with a skin rash and dermatomyositis, but there seems to be an overlap between clinical phenotypes, histopathology, and immunotypes. These observations suggest that there might be more than just one factor that determines the histopathological and clinical phenotypes, for example genes and environment.
From: Grundtman C, Malmstrom V, Lundberg IE. Immune mechanisms in the pathogenesis of idiopathic inflammatory myopathies. Arthritis Res Ther. 2007 Mar 26;9(2):208.

Overview - The immune response to the muscle cells:

Many doctors, including Dr. Dalakas, are proposing that sIBM is an autoimmune disorder characterized first by a T-cell inflammatory response. In sIBM, the muscle fibers display MHC class I antigens on their surfaces and that this creates an ongoing invasion of the muscle cells by CD8+ cytotoxic T cells that target and kill the muscle cells. These events are also associated with genes in the HLA-DR and DQ regions. Other autoimmune diseases are common in patients with sIBM and/or in their families. Dalakas is also suggesting that the antigens presented are consistent over time implying a persistent stimulation of the immune system by the same antigens. This idea was supported by the finding that the T-cells that invade the muscle cells have the specific rearrangement in the TCR gene for the recognition of these antigens. As of now, they do not know what these antigens are. Dalakas also notes that sIBM is mysterious because it does not respond to immunotherapies and this is confusing as, in theory, these sorts of drugs should help.
Reference: Amemiya K, Granger RP, Dalakas MC. Clonal restriction of T-cell receptor expression by infiltrating lymphocytes in inclusion body myositis persists over time. Studies in repeated muscle biopsies. Brain. 2000 Oct;123 ( Pt 10):2030-9.

IBM has been modeled as having cytotoxic T lymphocyte (CTL)-mediated destruction of MHC class I antigen expressing myofibers. In simple terms, this means that in sIBM, muscle cells (myofibers) display "flags" (called MHC class I antigens) on their surfaces alerting the immune system that they are infected or damaged and the immune system attacks them with CD8+ - CTLs. The CTLs secrete molecules that destroy the muscle cell. A virus might cause this sort of reaction but no virus has yet been discovered related to sIBM. It is also possible that sIBM is an autoimmune disorder and many believe that it is an autoimmune disease, in which the body's own immune system attacks healthy muscles. An antibody is a protein used by the immune system to identify and neutralize foreign objects like bacteria and viruses. Each antibody recognizes a specific antigen unique to its target. Antigens have sites on their surface called epitopes, that are part of class I histocompatibility molecules that interact with specific antibodies. Almost all the cells of the body express these class I molecules. CD8+ T cells bind to these sites. It is known that in the muscles of patients with sporadic inclusion body myositis (sIBM) some of the muscle fibres come to display an immune "flag" (antigen presentation) on their surface. Why? We don't know but the cause likely is either a virus or an autoimmune reaction. This flag starts a chain of events that leads to the long term activation of a response from the immune system. Immune cells see the flag (like a target) and invade the muscle cell with CD8+ cells and kill it.

• T lymphocytes (T cells)
  • include the subset of CD8+ cells
    • which include the subset of CTLs

Today, we see that "muscle is not just a passive target of immune reactions. On the contrary, muscle cells or myoblasts can express various cytokines, chemokines, adhesion molecules, and costimulatory
molecules upon immunological challenge. This enables them to actively participate in immune reactions, for example, as antigen-presenting cells. . . . "Moreover, the innate responses of muscle cells and their
armamentarium of cytokines, chemokines, and MMP do not only affect the mechanisms of immune surveillance but may also be involved in the processes of muscular degeneration and regeneration."
Reference: Bettina Schreiner et al, Expression of toll-like receptors by human muscle cells in vitro and in vivo: TLR3 is highly expressed in inflammatory and HIV myopathies, mediates IL-8 release, and upregulation of NKG2D-ligands. The FASEB Journal express article 10.1096/fj.05-4342fje. Published online November 17, 2005. Recent research (see What's New 2004, the article by Schmidt et al) strengthens the idea that sIBM is caused by some sort of problem in the immune system. This offers the chance that medications can be developed to target breaking a link in the chain of the immune interactions involved between seeing the flag and killing the muscle cell so that the destruction of the muscle cells could be stopped.

In summary, in sIBM, there is a long term activation of the bodies immune response, apparently directed toward specific antigens ("targets") on the muscle cells that leads to inflammatory reactions that in turn lead to progressive muscle destruction and weakness (see Muntzing et al, August 2003, Scandinavian Journal of Immunology 58, 195-200.) We see that the immune system mounts and continues to mount a consistent response for many years after symptoms (weakness) appear. So, what is the antigen responsible: what is the flag or trigger that causes the immune response? Generally, it is either to something foreign (like a bacteria or a virus) or it is an autoimmune disorder. In this model of sIBM, the protein abnormalities seen in the muscle cells are thought to be a secondary effect of the immune attack on the muscle cells, and not a cause of the sIBM.

- i). The Viral Infection Model of sIBM:

- The type of immune response seen in sIBM is similar to our response to certain types of viruses, especially retroviruses, thus, perhaps some undiscovered virus (or combination of viruses) infects the muscles and causes sIBM.

- "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." Dalakas, 2006 [See section 2-9]

- If it's a virus, why is IBM so rare? One reason could be that the virus is rare, or because only a few people get the virus (or combination of viruses). Second, the virus could be a more common type but the virus interacts with an individual's genetics and only a few people have the genetic disposition that interacts with the virus to produce sIBM. (Most people would have a genetic disposition that does not lead to any disease when combined with this unknown virus (or combination)). If there is a link between sIBM and Alzheimer Disease perhaps a virus causes both diseases, a few people may have the genetic disposition that interacts with the virus to lead to sIBM (pretty rare), while more people may have a genetic disposition that interacts with the virus to lead to Alzheimer Disease (Alzheimer is much more common than sIBM). This is all very open to conjecture.

- If it's a virus, why has it not been discovered? If it is HTLV-1, why have only 13 cases been discovered out of the thousands of people who have sIBM?

- Many viruses get into us and live inside us all of our lives. Some viruses seem to be "slow acting" and may take years before we see symptoms. So, this is not quite like catching a cold and getting sick and being better in two weeks. Perhaps the aging of the cells in the body makes us more vulnerable to the virus; it may be there all the time, but when we are young, we are able to fend it off, as we age, its effects are greater.

- ii). sIBM could be an autoimmune disorder:

In an autoimmune disorder, the body recognizes its own tissues as foreign and directs an immune response against them. It is possible that the immune reaction to the muscle in sIBM is an autoimmune reaction. Other important examples of autoimmune disorders include: Multiple sclerosis, Crohn's Disease, Myasthenia gravis, Ulcerative colitis, Guillain-Barré, Rheumatoid arthritis, Systemic lupus erythematosus, polymyositis, and dermatomyositis. See: http://www.niaid.nih.gov/publications/immune/the_immune_system.pdf

- iii). Pros and cons of sIBM as an inflammatory / immune system disease:

- Points for this idea:
= More and more research is establishing the immune reaction in sIBM.
= It is not clear yet what causes it, but the usual suspects are actively being investigated.

Dalakas, 2006 notes 10 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 same 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

 

- Points against this idea:
= sIBM is mysterious because it does not respond to immunotherapies that should help.

- Perhaps inflammation is not a primary feature, rather, it is a byproduct of some other chain of events. An initial cause may trigger a series of abnormalities that then cause the immune system reaction. In this case, the critical event that needs intervention (treatment) may occur BEFORE the immune system comes into play.
- There are still a lot of questions to be answered about the role of the immune system in sIBM.

sIBM as a protein disease:

- There is no doubt that there are many protein abnormalities seen in sIBM. The question is, is there an initial protein abnormality that causes the cascade of subsequent protein abnormalities and subsequent immune responses? Or, are the protein abnormalities the result of the immune system activation and attack or some other initial cause (a virus for example).

sIBM and stress inside the cell:

- Many diseases are mediated (made better or made worse by) by day-to-day stress. This is the kind of stress that we commonly understand when the term is used. If a person has high stress levels, the disease often is made worse. It is possible that high stress contributes to causing sIBM and/or to making it worse.

- There is another kind of stress scientists talk about that occurs inside the cell that has been implicated in sIBM. In the cell there is a system of interconnected membranes that transport materials called the endoplasmic reticulum. Proteins in the endoplasmic reticulum (ER) require an efficient system of molecular chaperones whose role is to assure their proper folding and to prevent accumulation of unfolded proteins. When unfolded proteins accumulate, it creates endoplasmic reticulum stress (ER stress or ERS). The response of cells to accumulation of unfolded/misfolded proteins in the ER is termed the "unfolded protein response" (UPR). Cells attempt to protect themselves against ER stress with the UPR.

- [In sIBM] 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. Reference: Dalakas, 2006

- Askanas and her team have proposed that the ERS is part of the IBM pathogenic cascade, occurring in response to abnormally unfolded or misfolded proteins; and that the UPR, occurs in a failed attempt to facilitate proper folding of malfolded proteins, and/or their disposal. Reference: Gaetano Vattemi, W. King Engel, Janis McFerrin and Valerie Askanas Endoplasmic Reticulum Stress and Unfolded Protein Response in Inclusion Body Myositis Muscle American Journal of Pathology. 2004;164:1-7.

Science 15 September 2006: Vol. 313. no. 5793, pp. 1564 - 1566, DOI: 10.1126/science.313.5793.1564
Endoplasmic reticulum (ER) and endoplasmic reticulum stress.
by: Jean Marx
Protein synthesis involves a lot more than stringing amino acids together in the right order. To function correctly, each linear strand of amino acids has to fold into just the right three-dimensional shape and may also have to be modified by addition of sugars or other accessory molecules.

Cells making proteins have mechanisms to maintain quality. Recently, cell biologists have learned a great deal about how the cell manages this quality control for the protein assembly line located within a convoluted network of membranous tubes known as the endoplasmic reticulum (ER). Roughly one-third of the cell's proteins, mainly those that end up in cellular membranes or are secreted to the outside, are made in the ER.

Researchers have shown that the ER membrane contains three separate sensor molecules that respond when excessive amounts of unfolded proteins build up inside. This can happen with mutant proteins, such as the ones that cause hereditary Alzheimer's and Parkinson's disease. But it can also occur under more normal conditions if for some reason proteins are synthesized faster than they can fold and be modified. To alleviate this "ER stress," the sensors trigger a series of signaling pathways that shut down the synthesis of most proteins while turning up the production of those needed for protein folding and degradation.

This so-called unfolded protein response (UPR) is intended to protect the cell, but it's not foolproof. Sometimes, for example, the UPR can't eliminate the abnormal protein buildup in the ER. In that event, prolonged activity of the UPR may trigger cell death and may thus contribute to the neuronal loss of Alzheimer's, Parkinson's, and other neurodegenerative diseases. And the UPR may even backfire by protecting the cells of cancerous tumors from the lack of oxygen and nutrients they experience as tumors grow.

In addition to cancer and neurodegeneration, ER stress and the UPR have been linked to several other common human ills, including diabetes and heart disease. In fact, the research has already suggested a new way to guide breast cancer therapy and hinted at a novel drug treatment for diabetes. "The field is expanding so much in terms of mechanism and relevance to disease. It's just popping up everywhere," says cell biologist Randal Kaufman of the University of Michigan Medical Center in Ann Arbor.

Synopsis of specific theories:

• sIBM could be caused by a virus that has not been discovered yet.
• sIBM could be a type of immune or autoimmune type of disorder.
• sIBM could be caused by a defect in one of the proteins needed for proper muscle function, leading to an immune reaction and cellular degeneration.
• Some combination of the above factors could be involved.
• There also appears to be a genetic predisposition -- there appear to be a number of sIBM "susceptibility genes," when present, they interact with environmental factors to increase the chances of sIBM developing, especially in "an aged muscle cellular environment,"that is to say, primarily occurring in older people.

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Part 2: Some Specific IBM Issues.

2-1). Possible Complications.

2-1 A). Dysphagia.

• Dysphagia means difficulty swallowing. Here is an excellent overview from the Outlook magazine (2003) of the Myositis Association of America.
• In from 40 to 85% of IBM cases, people will develop weakness in the pharyngeal muscles, the muscles used in swallowing, resulting in dysphagia.
• Dysphagia in IBM is common but underreported by the vast majority of patients if not specifically asked for. In practice, two questions reveal problems: 'Does food get stuck in your throat' and 'Do you have to swallow repeatedly in order to get rid of food'. See article here.
• This weakness is generally progressive and if present should be evaluated and reviewed for treatment.
• Dysphagia is characterized by food getting stuck "half way down" resulting in choking episodes. In some cases, during these episodes food gets drawn into the lungs, a situation called aspiration. When this happens, pneumonia often develops.
• In IBM patients, dysphagia is a significant cause of death from respiratory complications associated with aspiration pneumonia.

• The following general advice applies to anyone with IBM:
  • To reduce the risk of choking while eating, a few simple rules will help.
  • Eat in a very slow and deliberate manner, concentrated on what you are doing.
  • Before swallowing, take a drink to wet your throat.
  • Take small bites and chew well.
  • Above all, do not rush and do not speak or attempt to have a conversation while eating.
  • If you feel that food is not going down or is stuck, take a very small sip of liquid and swallow, this often loosens and lubricates the food to pass. Once the food has passed, take a larger drink to fully clear the throat.the
  • If possible, do not eat while alone.
  • Never eat in bed or while reclining.
  • Certain foods may be more difficult for you to swallow, if this is the case, either avoid these foods or be extra careful.
  • One recommendation is to eat foods in groups, for example, when eating a hamburger, separate the bun from the hamburger and eat them separately. The consistency of the food is important, especially of bread, doughnuts, potatoes and other doughy foods.
  • It is optimal if you speak to your companion in advance as to what to do if you do choke. Patting a person on the back is now seen as a marginal approach, the best technique is the Heimlich Maneuver.

• 

• 

• How to perform the Heimlich Maneuver on a Person in a Wheelchair
  • Step 1 Ask, "Are you choking?" to a person who is coughing, able to speak and not turning blue. A person who is choking will likely not be able to reply verbally.
  • Step 2 Remain calm and encourage the person to do the same. Try speaking to him or rubbing his back or arm to calm him.
  • Step 3 Look for signs that the person is suffering from total airway obstruction. These signs include the victim being unable to make any sounds above a wheeze, the face turning blue and hands clutching the throat in the universal symbol for choking.
  • Step 4 Engage the wheelchair's brake if it's not already on, or turn off a power chair.
  • Step 5 Try to perform the maneuver from the back, standing behind the person's wheelchair. If the back of the wheelchair is too high, do the maneuver from standing in front of the person (with him or her still sitting in the chair).
  • Step 6 Lean the person forward, moving her head and torso down at a slight tilt.
  • Step 7 Make a fist with one hand.
  • Step 8 Place your fist just above the person's navel with your thumb in contact with his body.
  • Step 9 Grab hold of your fist firmly with your other hand.
  • Step 10 Make a quick in-and-up thrust against the person's diaphragm. You may need to repeat thrusting several times before the object is expelled.
  • Step 11 Repeat until the choking person can breathe, the object is expelled or the person loses consciousness. If necessary, lay the person flat and do the maneuver as pictured above.
  • Step 12 Call for medical help using 911 or another emergency number if necessary.

• The feeling of choking often results in panic, when choking you need to tell yourself to relax and be as calm as possible until the episode can be resolved.
• Sadly, many elderly IBM patients with dysphagia develop malnutrition because they are afraid to eat, or eat foods that are nutritionally inappropriate but are easy to swallow, for example, ice cream.
• If you are an IBM patient and you feel you are developing difficulty swallowing you need to discuss this with your doctor who will refer you to a specialist for evaluation and treatment. Speech therapists often assess swallowing difficulties and there are tests that can be done, for example a barium swallow.
• Treatment may involve exercises or in some cases an operation on the throat.
  • There is a muscle at the top of the esophagus called the cricopharyngeus. This muscle is normally contracted, closing off the top of the esophagus. Normally, when a person swallows this muscle momentarily relaxes opening the top of the esophagus allowing food to pass into the stomach. In some cases, individuals who have trouble swallowing may have a procedure (a myotomy) to disable this muscle, facilitating the passage of food into the stomach.
• The latest article summarizing dysphagia in IBM, by Oh et al (2008) can be found here.
• A textbook on dysphagia.

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2-1 C). Falls.

Injuries caused by tripping and falling are a major risk in IBM patients. Three basic falling scenarios are described. Some patients benefit from leg or ankle braces (Knee-Ankle-Foot Orthosis - KAFO) or (Ankle-Foot Orthosis - AFO).

A KAFO is a long-leg orthosis that spans the knee, the ankle, and the foot in an effort to stabilize the joints and assist the muscles of the leg.

• Falls caused by toe drop.
  • Toe drop is the situation where when taking a step the toe does not rise high enough causing the toe to stub and the individual falls forward onto their knees. In IBM, this is caused by weakness in the muscles in my leg responsible for lifting the toe. These falls are often one of the first symptoms noticed by the patient with IBM. A common example is a person stepping up onto the curb and not having the foot go high enough causing the toe to bump into the curb and tripping.
• Falls caused by losing one's balance.
  • These falls are often experienced as in "slow-motion," you start to lose your balance and realize that you're falling but you cannot stop yourself and you slowly fall over "like a tree falling in the forest." These falls can often result in back and head injuries. Walking on uneven surfaces like lawns is difficult for the IBM patient causing these kinds of falls.
• Falls caused by collapse of the knees.
  • In these falls, the knees collapse without warning and you fall straight down, landing on top of your feet. These types of falls are often experienced instantaneously and you are on the ground before you feel that you are falling. These falls can easily result in knee and ankle injuries.

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2-1 D). Lifestyle Complications.

Also see the section on practical coping strategies

• It is important to realize that the effects of IBM on one's lifestyle may produce secondary issues.
  • For example, as mobility is restricted one's dietary intake should be reduced to avoid weight gain.
  • Restricted mobility, especially when using a wheelchair may be related to the development of edema in the lower legs and this should be monitored. Edema can be prevented or limited by the use of pressure stockings and the restriction of salt in one's diet.
  • Restricted mobility is also an issue in skin care. Skin is prone to damage from excess moisture and hygiene is particularly important as urine is a major irritant. Sitting for long periods of time in one position can cause creases and blisters in the skin. Finally, attention must be paid to sleeping as remaining in one position for long periods of time can result in the development of pressure sores. Pressure sores can result in the breakdown of skin or, in more serious cases, of underlying muscle tissue. These skin related complications can be very difficult to treat, therefore prevention is the best strategy.
    • IBM presents a significant risk of developing bed sores. Pressure sores or bed sores are a serious complication of people who are relatively immobile. As well, the major muscle atrophy in the thigh muscles seen in IBM adds to the risk. Pressure sores have several major aspects. One is the simple but constant pressure from gravity as it pulls the body down. In cases where it is difficult (or impossible) to move or turn over in bed, pressure sores can rapidly develop (in as little as 12 hours). In cases where there is major muscle atrophy, usually the hip bone pushes down on the thigh muscles (and skin) impairing the circulation and breaking the tissues down. The key to prevent this is to have a soft mattress and to move around enough that a "spot" of damage does not "buildup". In some cases, a special type of mattress surface can be used (often a rubber honeycomb type of pad that cushions the "boney spots.") These sores can also occur if you sit in a chair too long in one position. Another major issue is shear. Shear occurs when your body shifts its weight in one direction, but the skin does not move, it adheres to the surface under you. Sliding down in a bed or chair more than 30 degrees is especially likely to cause shearing, which stretches and tears cell walls and tiny blood vessels. Especially affected are areas such as your tailbone where skin is already thin and fragile. In IBM, shear is a problem as it is difficult to turn using the arms and as the natural tendency is to try to turn over in our sleep, the skin often "sticks" to the covers or mattress and shear forces are created (the body tilts over but the skin does not move (it feels like there is a piece of tape holding the skin from moving). The best solution to this problem is sleeping with the skin directly on a natural sheepskin. The best results are with a fairly thick pile (the thicker the cut, the better). The sheepskin also helps to prevent moisture (sweat) buildup, another major factor that contributes to skin irritation. If excessive mositure builds up, especially in the presence of urine or feces, there can be rapid skin irritation. In cases of IBM, pain perception is usually intact and you will feel your hip getting sore. Do not ignore these pain signals. Lack of pain perception and sensation is a major complication in some cases, usually involving spinal cord injuries or disease. Whatever the cause, an inability to feel pain means you're not aware when you're uncomfortable and need to change your position or that a bedsore is forming, This situation requires active management and careful monitoring.

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2-2). sIBM and Peripheral Neuropathy:

• Some neurologists believe that a significant group of patients with sIBM will also display another rare disease called a peripheral neuropathy: that the two rare diseases are somehow linked and tend to occur together.
• Dr. Todd Levine indicates that some 19% of IBM patients will have a peripheral neuropathy (page 4 of Outlook, The Myositis Association, Winter, 2008).
• This issue is controversial as any possible connection has not been published in the literature. (Ideally, if the connection is "real" it should be seen and well documented with published research and be recognized by a large group of neurologists). Few references talk about a connection.
• Hermanns B, Molnar M, Schroder JM. "Peripheral neuropathy associated with hereditary and sporadic inclusion body myositis: confirmation by electron microscopy and morphometry." J Neurol Sci. 2000 Oct 1;179(S 1- 2): 92-102. Recently, another article also mentions it: Engel, W King MD; Askanas, Valerie MD, PhD. Inclusion-body myositis: Clinical, diagnostic, and pathologic aspects. Neurology Volume 66(2) Supplement 1 January 24, 2006 S20-S29.
• When I saw Dr. Engel in Los Angeles, he indicated to me that they look for a peripheral neuropathy (CIDP) in all of their sIBM cases and that over the years, he has seen some 150 cases with both diseases (although he has not published this finding).

• Chronic Immune Demyelinating Polyneuropathy (CIDP): A disease involving de-myelination of the peripheral nerves (both sensory and motor). Causes weakness in the arms and legs and sometimes sensory problems (tingling in the hands and feet). A more chronic form of Guillain-Barré Syndrome. CIDP is a sporadic acquired Polyneuropathy that presents with both proximal and distal weakness and impaired tendon reflexes in the extremities. In addition, sensory loss is usually present, most often with deficits to vibration and touch. The pathogenesis of this disease is presumed to be autoimmune, with evidence of both cell-mediated and humoral processes, but the mechanism is unknown.
• CIDP is called a neuropathy: it is a disease that affects the nerves in the body. Nerves and muscles function together, so a connection between a muscle and a nerve disease would not be a total shock.
• CIDP has some similar symptoms to sIBM.
• CIDP is usually treated with IVIG and as I understand it, tends to respond well to this treatment.
• Some patients treated for sIBM report that they feel stronger. It could be the case that patients with sIBM who respond to IVIG treatment are getting a bit better because they also have CIDP and it is responding to the drug (not the sIBM).
• As I understand it, CIDP is somewhat like multiple sclerosis (MS) in that the myelin of the nerve is being affected, but in MS, the nerves of the central nervous system (CNS) are affected (the spinal cord and the brain) while in CIDP, it is the peripheral nerves (sensory and motor) that are affected (the nerves that go out to the arms and legs). CIDP is a de-myelination of the peripheral nerve
• In the peripheral nerve the myelin is built up by Schwann cells, and these cells are affected in CIDP
• The Schwann cells degenerate and so, some neurologists call it Chronic immune (or inflammatory) dysschwannian polyneuropathy.
• For more information on CIDP.

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2-3). sIBM and Prion Protein:

Overview: A protein called prion protein (labeled PrP or PrPc), is normally found in human cells. Research has discovered that people with sIBM show increased levels of prion protein in their muscles. Abnormal forms of the prion protein (labeled PrPsc) have been linked to a series of brain diseases, in cattle called Bovine Spongiform Encephalopathy (BSE) ("Mad Cow Disease"), and in humans, a similar disease called Creutzfeldt-Jakob Disease (CJD). In 2001 a group of Italian researchers looked at the prion protein in sIBM patients and found that although its level was increased, it was the normal form. In 2004, the case of a man with both sIBM and CJD was examined. He had increased levels of the abnormal form of the prion protein in his muscle (not just in his brain as would be expected). It was suggested that because his levels of normal prion protein were increased in his muscles (due to his sIBM), that it was somehow easier for his CJD disease to convert the normal muscle prion into the abnormal prion form (this conversion occurring due to him having CJD).

Update:

Cellular prion protein regulaes (beta) -secretase cleavage of the Alzheimer's amyloid precursor protein
Edward T. Parkin*, Nicole T. Watt*, Ishrut Hussain§, Elizabeth A. Eckman, Christopher B. Eckman, Jean C. Manson,
Herbert N. Baybutt, Anthony J. Turner*, and Nigel M. Hooper
[The level of normal prion protein (PrP) in muscle has been reported to be elevated in patients with inclusion-body myositis. (beta) amyloid protein is thought to play a major role in Alzheimer disease and certainly is implicated in IBM. Now, research shows that the production of (beta) amyloid protein is regulated by normal prion protein. The research referenced below, found that high levels of normal prion proteins in human cells prevent (beta) amyloid formation. Conversely, mice genetically modified to lack normal prion protein had significantly higher (beta) amyloid levels. The research notes that this may have implications for both Alzheimer's (the focus of this research) as well as for the prion diseases. Obviously, given prion proteins elevated production in IBM this finding seems relevant here as well.]

Proteolytic processing of the amyloid precursor protein (APP) by (beta) -secretase, (beta) -site APP cleaving enzyme (BACE1), is the initial step in the production of the amyloid (beta) (A (beta) ) peptide, which is involved in the pathogenesis of Alzheimer's disease. The normal cellular function of the prion protein (PrPC), the causative agent of the transmissible spongiform encephalopathies such as Creutzfeldt- Jakob disease in humans, remains enigmatic. Because both APP and PrPC are subject to proteolytic processing by the same zinc metalloproteases, we tested the involvement of PrPC in the proteolytic processing of APP. Cellular overexpression of PrPC inhibited the (beta) -secretase cleavage of APP and reduced A (beta) formation. Conversely, depletion of PrPC in mouse N2a cells by siRNA led to an increase in A (beta) peptides secreted into the medium. In the brains of PrP knockout mice and in the brains from two strains of scrapie infected mice, A (beta) levels were significantly increased. Two mutants of PrP, PG14 and A116V, that are associated with familial human prion diseases failed to inhibit the (beta) -secretase cleavage of APP. Using constructs of PrP, we show that this regulatory effect of PrPC on the (beta) -secretase cleavage of APP required the localization of PrPC to cholesterol-rich lipid rafts and was mediated by the N-terminal polybasic region of PrPC via interaction with glycosaminoglycans. In conclusion, this is a mechanism by which the cellular production of the neurotoxic A (beta) is regulated by PrPC and may have implications for both Alzheimer's and prion diseases.

Update:

PNAS April 17, 2007 vol. 104 no. 16 pps. 6800-6805.
Inducible overexpression of wild-type prion protein in the muscles leads to a primary myopathy in transgenic mice.
Shenghai Huang, Jingjing Liang, Mengjie Zheng, Xinyi Li, Meiling Wang, Ping Wang, Difernando Vanegas, Di Wu, Bikram Chakraborty, Arthur P. Hays, Ken Chen, Shu G. Chen, Stephanie Booth, Mark Cohen, Pierluigi Gambetti, and Qingzhong Kong.
The prion protein (PrP) level in muscle has been reported to be elevated in patients with inclusion-body myositis, polymyositis, dermatomyositis, and neurogenic muscle atrophy, but it is not clear whether the elevated PrP accumulation in the muscles is sufficient to cause muscle diseases. We have generated transgenic mice with muscle-specific expression of PrP under extremely tight regulation by doxycycline, and we have demonstrated that doxycyclineinduced overexpression of PrP strictly limited to muscles leads to a myopathy characterized by increased variation of myofiber size, centrally located nuclei, and endomysial fibrosis, in the absence of intracytoplasmic inclusions, rimmed vacuoles, or any evidence of a neurogenic disorder. The PrP-induced myopathy correlates with accumulation of an N-terminal truncated PrP fragment in the muscle, and the muscular PrP displayed consistent mild resistance to protease digestion. Our findings indicate that overexpression of wild-type PrP in skeletal muscles is sufficient to cause a primary myopathy with no signs of peripheral neuropathy, possibly due to accumulation of a cytotoxic truncated form of PrP and/or PrP aggregation. accumulation of PrP in the muscle fibers (19). The present study reports that strictly muscle-specific overexpression of wild-type human PrPC [the normal or cellular prion protein] under tight regulation by doxycycline in Tg mice leads to a primary myopathy. These data argue that overexpression of wild-type PrP in the skeletal muscle is in itself sufficient to cause a myopathy. Our data demonstrate that overexpression of wild-type PrP [PrPC ] in the skeletal muscles alone is sufficient to cause myopathy. These findings strongly suggest that the elevated levels of PrP found in the skeletal muscles of human primary myopathies, such as inclusion body myositis (3 to 5) and inflammatory myopathies including polymyositis and dermatomyositis (5), may play an important role in the pathogenesis.

Background: Prion protein (PrP or PrPc) is a normal part of cells in mammals. It can become abnormal and is then referred to as PrPsc. Stanley Prusiner has suggested that this abnormal protein alone can cause infections leading to severe diseases. This has been controversial and many scientists initially disagreed with this theory, suggesting that a virus of some sort must also be involved. Recent evidence (Science July 30, 2004) confirms that the abnormal prion protein alone appears to be a sufficient single cause of the problems and that no other virus is needed for infection. Creutzfeldt-Jakob {KROITS- Felt Ya- Cop} disease (CJD): A rare, degenerative, life-threatening brain disorder characterized by severe, progressive dementia; visual disturbances; muscle weakness; and abnormal involuntary movements, such as sudden, brief, "shock-like" muscle spasms (myoclonus), tremor, and relatively slow writhing motions that appear to flow into one another (athetosis). Most frequently, Creutzfeldt-Jakob disease is thought to erupt spontaneously (sporadically), (sCJD) with no detectable cause, although, about 10 percent of cases are familial, suggesting a hereditary predisposition to the disease. Evidence suggests that CJD is somehow caused by abnormalities of the human prion protein gene or contamination with abnormal prion protein (PrPsc) ("prion" was named for "protein infectious agent"). Changes in the prion protein appear to lead to distinctive neurodegenerative abnormalities, i.e., some regions of brain tissue have relatively small, round, "sponge-like" (spongiform) cavities or gaps and looks like a sponge. CJD belongs to a group of related neurodegenerative disorders categorized as "transmissible spongiform encephalopathies." Similar diseases can occur in other animals, for example, bovine spongiform encephalopathy (BSE) (seen in cattle: the so-called "mad cow disease"); Scrapie (in sheep); Chronic wasting disease (in deer); Feline spongiform encephalopathy (FSE in house cats). In rare cases, CJD in humans may has resulted from exposure to contaminated surgical instruments during brain surgery and was also reported in the past due to therapy with pituitary-derived human growth hormone. In addition, a variant form of CJD (V-CJD or nV-CJD) has been reported, primarily in the United Kingdom. V-CJD is a human disease linked to the consumption of material from cows with bovine spongiform encephalopathy (BSE). To date, at most, only a few hundred cases of nV-CJD have been seen in humans. In 2001, an Italian group of researchers lead by Zanusso looked at the prion in patients with sIBM. Increased amounts of prion protein expression and deposition have been described in pathological muscle fibers of two human muscle disorders: sporadic inclusion-body myositis (s-IBM) and hereditary inclusion-body myopathy. They found only the normal form of the prion (PrPc), and not the abnormal (PrPsc) form in s-IBM. The researchers concluded that "the present results exclude that s-IBM is a prion disease". Reference: Zanusso G, et al, "Increased expression of the normal cellular isoform of prion protein in inclusion-body myositis, inflammatory myopathies and denervation atrophy". Brain Pathol. 2001 Apr;11(2):182-9. In a recent (2004) case study of a 68 year old man who had both sCJD and sIBM, the abnormal form of prion protein was found outside of his neural tissues and was found in his muscle (we would expect it in his brain because of his CJD, but finding it in his muscles and outside of his nervous system was a first). Pathological prion protein (PrPsc) is the hallmark of prion diseases affecting primarily the central nervous system. Researchers demonstrated abundant PrPsc (abnormal prion) in the muscle of this patient with sporadic Creutzfeldt-Jakob disease and inclusion body myositis. The researchers conclude that "Extraneural (outside of the nervous system) conversion of PrPc to PrPsc in Creutzfeldt-Jakob disease appears to become prominent when PrPc is abundantly available as a substrate, as in inclusion body myositis muscle." Reference: Kovacs GG et al, Creutzfeldt-Jakob disease and inclusion body myositis: abundant disease-associated prion protein in muscle. Ann Neurol. 2004 Jan;55(1):121-5. The role of prion (PrPc) in normal muscle and the role of increased PrPc in muscles in sIBM is unknown at present. This line of research will be interesting to watch.

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2-5). sIBM as an immunological versus a neurological / neuromuscular disease:

Many patients are referred to neurologists, many also happen to be referred to a rheumatologist and many see both types of doctors. There can be fairly major differences in clinical approaches (how the doctor approaches the disorder and treats you) between these two specialties. These differences also mirror the basic theories of sIBM: if it is an immune disease of some sort, then it traditionally falls more into rheumatology. If it is a muscular problem then it falls more into neurology. Both types of doctors are trying to understand and treat sIBM. Does it matter what kind of doctor you see? -- probably not as both kinds are capable of diagnosing IBM.

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2-6). sIBM and Alzheimer disease (AD):*

• Researchers have suggested that both sIBM and Alzheimer Disease (AD) display some major biochemical similarities in the protein abnormalities seen (as well as some major differences). Based on these similarities, some researchers believe that the two diseases are somehow related: the theory is that you get this chain of abnormalities started somehow and then, in one case the disease goes on to affect muscle (sIBM: very rare), and in the other case, it goes on to affect brain cells and it eventually develops into AD (much more common than sIBM).
• Dr. Askanas has referred to AD as "sIBM of the brain" and sIBM as "Alzheimer's of the muscle."
• Part of this connection is the apparent accumulation within s-IBM muscle fibers of several abnormal proteins, including; amyloid- (beta) (A (beta) ), phosphorylated tau, and at least 20 other proteins that are also accumulated in Alzheimer brain. If the same abnormal proteins accumulate within IBM muscle fibers as accumulate in the brain of AD patients, the muscle and the brain diseases might share certain pathogenic steps, and knowledge of one disease might help unravel the other. As well, cellular aging and evidence of oxidative stress are associated with both IBM and AD. Both IBM and AD include sporadic and hereditary forms, and both are considered multifactorial and polygenetic diseases.
• In AD, it has been suggested that abnormal cellular processing of amyloid (beta) precursor protein (amyloid (beta) PP) leads to the release of amyloid (beta) from the brain cells which then aggregates into sheets of A (beta) found outside of the brain cells (it is found between the cells). For years it has been hypothesized that this extracellular (outside the cells) amyloid (beta) somehow contributes to AD. Emerging evidence now suggests that amyloid beta may also accumulate intraneuronally (inside the individual neurons) and that this may also contribute to the progression of the disease (LaFerla, 2007). If this is the case, this accumulation of amyloid beta inside the cell would mirror the process that has been suggested in IBM.
• Several years ago Askanas and Engel proposed that the accumulation of amyloid (beta) PP inside the muscle cells plays a key central role in the IBM pathogenic cascade. There are no amyloid (beta) containing plaques found in s-IBM outside of the muscle cells.
• The respective cascades of events leading to pathologic aspects are not yet understood in either disease. Aggregation of proteins, protein misfolding, and proteasome inhibition have been proposed to contribute to the development of both s-IBM and the AD. Yet each disease remains organ-specific, involving either muscle fibers or brain cells (neurons).
• IBM patients do not appear to develop Alzheimer's and AD patients do not appear to get IBM. The tissue affected, muscle vs brain, may be influenced by: 1) etiologic agent (a virus), 2) previous exposure to environmental factor(s), and 3) the patient's genetic background (the cellular microclimate). Thus, there does not appear to be an overlap at the end stage of the diseases: people with sIBM do not appear more prone to develop AD or visa versa. Dr. Askanas said in an April 2002 Quest article: "We personally have never seen IBM patients with Alzheimer's disease; nor have our colleagues I have talked to. That's very important. I'm not so brave as to say that IBM protects against Alzheimer's disease, but I can say that IBM does not predispose one to Alzheimer's. She went on: "In regard to IBM, I'm developing a hypothesis now that there are predisposing genes to different diseases, not disease-causing genes but disease-predisposing genes, and that there's one set that predisposes people to IBM and a different set that predisposes them to Alzheimer's disease. What I think is happening is that some genes direct a disease process to occur in aging muscles, and another set of genes directs a disease process to occur in the aging brain." See: http://www.mda.org/Publications/Quest/q82ibm.html
• As research unfolds, the possible relationship between amyloid beta and sIBM and AD will be clarified. As well, this research may open up new avenues of treatment for both diseases, if medications can be developed to reduce abnormal protein accumulation or break up inclusions, perhaps both diseases can be helped. Note: a recent publication by Greenberg (2009) addresses limitations in the beta-amyloid-mediated theory of IBM myofiber injury.
• * this section is paraphrased from: Askanas, and Engel, (2006).

Here are two pertinent figures from LaFerla (2007) describing the role of amyloid beta in Alzheimer.

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2-7). sIBM as an age related disorder - oxidative stress and proteostasis.

Aging in general is a very complicated concept and process that occurs on many different levels, from the level of the cell to the level of the whole organism. Generally speaking, aging is related to the number of cellular divisions that occur -- our body's cells divide and reproduce and, as they do, they age. The analogy of a Xerox is perhaps appropriate -- if you copy a page and then copy each successive copy again and again, the first copies are excellent but eventually, the quality of the image deteriorates and after enough copies the image becomes hard to read. Similarly, eventually, as cells reproduce they lose their dividing potential and eventually age just as our Xerox becomes fuzzier and fuzzier. There appear to be complex cellular and genetic mechanisms that control this aging process -- this aging process is natural -- it is built into our cellular mechanisms.

Part of the control of aging is now understood to be genetic -- each chromosome of DNA has a structure on its end called a telomere that acts like a bookend, protecting the end of the chromosome and preventing it from binding with other DNA. Each time a cell divides, the DNA is unwrapped and copied, however the telomeres are not copied in this replication process. In dividing, the DNA is clipped and this clipping occurs at the site of the telomere, therefore when the DNA rewraps the core of the DNA remains identical but the telomere has lost a bit of material and becomes shorter. After about 50 or 60 replications, the telomeres's shortness becomes an issue -- like a pencil eraser that has been used about 50 or 60 times and now is essentially worn off and can no longer perform its normal function. One of the confusing aspects of biology is that cancer produces an enzyme called telomerase that prevents the telomere from shortening -- hence, cancer cells do not age the way normal cells do and essentially are immortal, reproducing over and over without end.

There are several central mechanisms related to aging and implied in age-related disorders. I will currently only highlight two examples, oxidative stress and proteostasis.

Oxidative stress

One aspect of aging is related to normal cellular metabolism which is based upon the consumption of oxygen. In a cell, structures called mitochondria are the main energy factories, producing a chemical called adenosine triphosphate (ATP) that is the main source of chemical energy in the cell. The chemical mechanisms involved in this process use oxygen and a very small percentage of these chemical reactions create what are called partially reduced forms of oxygen. As it turns out, these odd forms of oxygen are extremely toxic and poisonous to the cell. They are sometimes referred to as free radicals. Normally, cells maintain a delicate balance between the formation of these chemical products -- oxidant formation -- versus oxidant elimination. Cells contain a number of natural antioxidant defenses designed to deal with the formation of these oxidant forms and to maintain this delicate balance.Young cells appear to be able to maintain this balance quite effectively. However, as cells age they become less capable of dealing with these chemical products and become more susceptible to damage from free radicals.

Because the mitochondria are the main source of these reactions in the cell, they often are the first to be impacted by free radical damage. This mitochondrial damage has been implicated in aging in general and in a number of age related disorders, including many movement and neurodegenerative disorders.

It has become popular to talk about antioxidants in food (for example, foods high in vitamin C and E and (beta)-carotene) and in supplements (for example, coenzyme Q10 and creatine) as the idea is that adding antioxidants to one's diet will help boost the normal cellular processes, improving the cell's ability to deal with oxidation and thus, in a sense delay aging. Research has demonstrated this approach increases the lifespan of different animals but no human study has yet demonstrated a change in human mortality rates. Research on age related diseases using antioxidant supplements has been encouraging (for example, in Parkinson's disease) but research is in its early stages and no clear trends are confirmed yet.

Superoxide dismutases (SODs).
Manganese Superoxide Dismutase (MnSOD) is an anti-oxidant enzyme, one of the primary defenses used by cells to protect mitochondria against the effects of free radicals. Other antioxidant enzymes include copper superoxide Dismutase and zinc superoxide Dismutase.
A research study done by Tsuruta (2000) found that the expression of copper and zinc superoxide dismutase as well as Manganese Superoxide Dismutase increased in cases of inclusion body myositis. The study concluded that Mn-SOD may have an important role as a protective response against nitric oxide-induced oxidative stress in IBM. The study further concluded that Cu, Zn-SOD and Mn-SOD may have different roles against oxidative damage in vacuolated muscle fibers in IBM.

This description will not delve into the complex science or chemistry involved in these reactions. But several terms are important to understand -- these toxic forms of oxygen are sometimes called reactive species or oxidants and the term free radicals has been used to describe this whole group of chemicals. By definition, a radical is a molecule possessing an unpaired electron -- this is a problem because this unpaired electron is looking for a mate and will react with a number of other chemicals that it runs into - it is called highly reactive. When these reactions happen in a cell it often disrupts the normal chemical processes going on. To be accurate, not all free radicals are strong oxidants and not all oxidants are radicals.

Not all reactive species are pathological -- in fact, the body has developed a critical function for reactive species -- in inflammation, reactive species and strong oxidants are created and used by the body's immune host response to kill invading microorganisms. Conditions that involve chronic inflammation may predispose secondary illness, in part, by producing too many strong oxidants.

As the balance of oxidation versus oxidant elimination tips toward oxidation (that is, as the cell falls behind and is overwhelmed by oxidation) a condition called oxidative stress occurs. Oxidative stress created by reactive species has been implicated in a number of disease conditions including sporadic inclusion body myositis. The protein inclusions of sIBM include a number of markers characteristic of oxidative stress.The idea that oxidative stress may be implied in sIBM is logical as sIBM is clearly an age-related disorder and the problems created by oxidative stress clearly also increase with age. Oxidative stress is one possible mechanism (among others) that may induce unfolded or mis-folded proteins -- the kind that characterize sIBM.

Proteostasis

At the heart of all organic processes are proteins. There are a number of complex steps in the creation, operation and ultimate disposal of proteins within the cell. A careful balance or homeostasis of protein is critical -- this is called proteostasis. As proteins are produced, they are vulnerable to abnormalities in their shape. Within the cell, there are complex mechanisms designed to help correctly form proteins and to watch for and deal with proteins that are abnormally formed. The final shape of a protein is critical to its function and misformed or misshaped / misfolded proteins cannot function and are usually broken down and disposed of by the cell. In addition, proteins are vulnerable to damage after they form and as they wear out, therefore they must be continually recycled, old proteins are broken down and disposed of and replaced by new protein created by the cell. In some cases, these damaged and misshaped proteins won't fit through the cellular "protein garbage disposal" and therefore end up accumulating -- researchers call it aggregating -- into lumps, plaques or inclusion bodies. These abnormal protein structures eventually disrupt the cell's normal biochemical mechanisms and may contribute to the ultimate death of the cell.

Again, we see that the cellular mechanisms that deal with protein shape are age related -- their effectiveness declines with age and the capacity for the cell to effectively manage abnormal protein declines as the cell ages. Therefore, a number of disorders that are age-related are also characterized by protein abnormalities and inclusions of abnormally formed or shaped protein including sporadic inclusion body myositis. Researchers are studying the regulators involved in these protein mechanisms to see if they could boost regulators to help deal with the increase in abnormally shaped proteins that increase as people age and in age-related disorders.

In the case of sporadic inclusion body myositis, several things are clear:

• it is an age-related disorder
• evidence of oxidative stress is seen
• mis-folded and aggregated protein appears to be a major component of the disorder
• an immune reaction to the muscle cells is a major part of the disorder

The critical question remains: what triggers sIBM in the average person who gets it and what role is played by the immune system -- is it part of the trigger or is it simply part of the response? Research will have to answer these questions before a better understanding of sIBM can be advanced.

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2-8). The Major Histocompatibility Complex (MHC).

Overview.

• From Needham et al (2007): The MHC is densely packed with immunologically important genes. The extended MHC has been associated with over 100 diseases, most of which are immune-mediated. This is not surprising, given that 28% of the 252 transcripts encoded by genes in the extended MHC are immune-related. The association of polymorphic variants of genes within the MHC with autoimmune disease often relates directly to the important role that MHC molecules play in regulating the types and degree of immune responses to environmental agents, T-cell receptor repertoire development, and peripheral tolerance to self antigens. It has been speculated that dysregulation of MHC-mediated immunological recognition events contributes to a breakdown of self-tolerance and the resultant development of autoimmune pathology.
• Diseases that have been demonstrated to have MHC associations include type 1 diabetes, ankylosing spondylitis, Graves' disease, Addison's disease, and myasthenia gravis.

The 8.1 ancestral haplotype is strongly associated with sIBM.

• Within the MHC are a series of groups of genes called ancestral haplotypes (AH) that have been conserved during evolution and occur commonly throughout the population.
• The AH characterized by HLA-A*01, -B*0801, -DRB1*0301, -DQB1*0201, -DQA1*05 (referred to as the 8.1 AH), is considered the 'autoimmune haplotype' in Caucasians because it has been associated with many different autoimmune diseases. The 8.1 AH is common in Caucasian populations, particularly those of Northern European origin. This haplotype has been associated with a number of variations in immunological function including an alteration in the cytokines produced, as well as differences in the early stages of cellular activation.
• "The strong association of HLA-DR3 and the extended 8.1 AH with sIBM was first reported in 1994 by Garlepp et al (1994). This association between sIBM and alleles characteristic of 8.1 AH has subsequently been confirmed in a number of studies." Reference: Needham et al (2007).

Summary:

• Studies of sporadic inclusion body myositis (sIBM) have shown a strong association with a group of related genes (a haplotype) on the short arm of chromosome # 6 called the HLA complex, part of a larger area called the 8.1 ancestral haplotype. HLA stands for "Human Leukocyte Antigen" This section of genes is largely responsible for the presentation of "foreign" peptides to the immune system. Previous research showed a strong association of sIBM with a specific area of the region, called HLA-DR3 (DRb1*0301) and this has been regarded as evidence of a primary autoimmune pathogenesis (cause) for sIBM.
• 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. Dalakas, 2006
• For more background on this topic, please see: The ancestral haplotype and sIBM.

• Major Histocompatibility Complex (MHC) on chromosome # 6
  • 8.1 ancestral haplotype (AH)
    • Subsection Human Leukocyte Antigen (HLA)
      • Subsection HLA-DR3 linked to sIBM
      • Other areas also identified as linked to cases of sIBM:
        • HLA-DR52, 35.2 AH, etc.

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2-9). IBM and HIV Related Viruses.

sIBM, HIV-1 and HTLV-1.

• Dalakas, 2006 said: "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."
• In the early 1980s, HTLV-1 was one of the first viruses linked to AIDS. Subsequent research found that a different virus causes AIDS (HTLV-III, they eventually called it Human immunodeficiency virus: HIV). Researchers later found that HTLV-1 causes an acute leukemia that is usually fatal within a year. The virus also causes a rare disease of the central nervous system called tropical spastic paraparesis, or HTLV-1 associated myelopathy, its symptoms include a progressive weakening of the extremities and peripheral sensory loss. In 1996, researchers looking for a virus in sIBM patients found that a few people who have HIV-1 or HTLV-1 also develop sIBM (as of 2005, up to 13 cases have been seen). Researchers "conclude that sIBM occurs in HIV-1 and HTLV-1 infected individuals and has a clinical, histological and immunological pattern identical to sporadic IBM in the non-retrovirally infected patients. Retroviruses do not directly infect the muscle, but persistent retroviral infections may provide superantigenic stimulation and trigger an endomysial inflammatory response identical to that occurring in sporadic IBM." Cupler et al (1996).
• Detailed analysis of inflammatory cells in blood and muscle was performed in one HTLV-1 infected patient who developed s-IBM. This appears to "strongly support" the concept that some sort of a chronic viral infection and immune recognition may be crucial to the inflammatory process that leads to s-IBM. Ozden et al (2004).
• The exact relationship between HIV-1 and HTLV-1 and sIBM is unknown at present. This line of research will be interesting to watch.

"HIV-IBM."

Dalakas et al (2007) have reported the association of sIBM with human immunodeficiency virus (HIV) infection.

Dalakas maintains that some kind of chronic viral infection in genetically susceptible individuals might trigger sIBM. Evidence is accumulating that the virus is some sort of retroviruse(s). This research is suggesting that HIV may be the first virus discovered to do this (? along with HTLV-1 ?), causing "HIV-IBM." But Dalakas is also leaving the door wide open in terms of other viruses, presumably there is another retrovirus candidate that is much more common than HIV (or HTLV-1) that will be discovered in the future. The four HIV patients in this study ALSO presented with symptoms of IBM and were ALSO diagnosed with IBM so, they were the natural people to study. I think what Dalakas is saying is that in these four people, HIV *caused their IBM,* but that there are likely other, yet undiscovered, retroviruses that will be discovered that will be linked to other sIBM cases. Again, if you studied other IBM patients "enough," eventually another [retro] virus (or multiple other viruses) might be discovered. Let's say for illustration retrovirus Able Baker is discovered to be linked to IBM, so, it may be that we have a number of IBM variants;

HIV-IBM,
HTLV-1-IBM,
Able Baker-IBM,
Able Charlie-IBM,
etc??.
etc??.

Here are a number of excerpts extracted from his March 2007 report (Dalakas et al, 2007).

• Studies in four HIV-infected patients with IBM were performed.
• The cause of sIBM is unclear, but two processes, one autoimmune and the other degenerative, appear to occur in parallel resembling primary progressive multiple sclerosis. Because sIBM is resistant to immunotherapies, it remains unclear which is the primary process, the degenerative or the inflammatory.
• The closest connection with viruses has been the observation that sIBM can be seen in association with HIV and human T-lymphocytic virus type 1 (HTLV-1) infection, two neurotropic viruses with different disease pathogenesis and distinctive character resulting in immune dysregulation or immunodeficiency.[21] Because these retroviruses were not detected within the muscle fibers, it was concluded that they did not directly infect the muscle, but rather triggered an inflammatory response against muscle.[21] Since our first description of three IBM cases in patients with retroviruses almost 10 years ago,[21] there have been at least three other cases reported,[22-24] and we have been referred nine more cases, suggesting that this association is not fortuitous.
• We now report studies in four new cases of sIBM in patients with HIV infection and describe the molecular mechanism of viral-specific T cells that invade the muscle fibers. We provide evidence that the autoinvasive CD8+ T cells are clonally expanded and viral specific, and invade muscle fibers that express MHC-I antigen. The findings shed light on the role of viruses as triggering factors in sIBM.
• We report four cases of sIBM in HIV-positive patients and demonstrate that clonally expanded and viral-specific CD8+ T cells are recruited within the muscle to surround or invade muscle fibers. The observations suggest that in sIBM, thought by some to be a strictly degenerative disease, viruses (HIV may be the first identified example) can trigger a viral-specific inflammatory response that may lead to disease initiation.
• Cumulative evidence indicates that sIBM occurs in a setting of retroviruses.
• Both HIV-IBM and sIBM are characterized by identical immunopathology of clonally expanded CD8+ T cells invading MHC-I-expressing muscle fibers.[39] These observations that some of the autoinvasive CD8+ T clones are viral specific suggests that a chronic viral infection in genetically susceptible individuals can trigger a persistent T-cell-mediated inflammatory process that could lead to development of sIBM. A similar mechanism has been proposed for sIBM occurring with HTLV-1 infection.[22][40] As in sIBM where the clonally expanded T cells persist even in different muscles for several years,[10][11] we found that in HIV-IBM the inflammation also persists over time based on repeated muscle biopsies, perhaps driven by the same antigenic stimuli, that is, viral peptides cross-reacting with specific muscle antigens. The chronicity of the infection and the recruitment of specific T-cell populations within the muscle may be essential for the development of such an indolent disease as sIBM.

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Webpage References.

Amemiya K, Granger RP, Dalakas MC. Clonal restriction of T-cell receptor expression by infiltrating lymphocytes in inclusion body myositis persists over time. Studies in repeated muscle biopsies. Brain. 2000 Oct;123 ( Pt 10):2030-9.

Askanas V, Engel WK. (2007) Inclusion-body myositis, a multifactorial muscle disease associated with aging: current concepts of pathogenesis. Curr Opin Rheumatol 19:550-559. (Major Review)

Askanas, V. and Engel, W. K., Inclusion-body myositis: a myodegenerative conformational disorder associated with A-beta, protein misfolding, and proteasome inhibition. Neurology 66 (suppl. 1): S39-S48, 2006.

Askanas V, Engel WK. Proposed pathogenetic cascade of inclusion-body myositis: importance of amyloid- (beta) , misfolded proteins, predisposing genes, and aging. Curr Opin Rheumatol 2003; 15:737-744.

Cupler EJ, Leon-Monzon M, Miller J, Semino-Mora C, Anderson TL, Dalakas MC. Inclusion body myositis in HIV-1 and HTLV-1 infected patients. Brain.1996 Dec;119 ( Pt 6):1887-93.

Dalakas, MC , Goran Rakocevic, MD, Alexey Shatunov, PhD, Lev Goldfarb, MD, Raghavan Raju, PhD, Mohammad Salajegheh, MD Inclusion body myositis with human immunodeficiency virus infection: Four cases with clonal expansion of viral-specific T cells. Annals of Neurology Early View (Articles online in advance of print) Published Online: 15 Mar 2007.

Dalakas, MC (August, 2006) Sporadic inclusion body myositis - diagnosis, pathogenesis and therapeutic strategies. Nature Clinical Practice Neurology 2: 438. (Major Review)

Ferrer I, Martin B, Castano JG, et al. Proteasomal expression, induction of immunoproteasome subunits, and local MHC class I presentation in myofibrillar myopathy and inclusion body myositis. J Neuropathol Exp Neurol 2004; 63:484-498.

Fratta P, Engel WK, Van Leeuwen FW, et al. Mutant ubiquitin UBB+1 is accumulated in sporadic inclusion-body myositis muscle fibers. Neurology 2004; 63:1114-1117.

Garlepp MJ, Laing B, Zilko PJ, Ollier W, Mastaglia FL. HLA associations with inclusion body myositis. Clin Exp Immunol 1994;98:40-5.

Greenberg SA. Inclusion body myositis: review of recent literature. Curr Neurol Neurosci Rep. 2009 Jan;9(1):83-9.

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Kovacs GG, Kalev O, Gelpi E, et al. The prion protein in human neuromuscular diseases. J Pathol 2004; 204: 241-247.

Kovacs GG et al, Creutzfeldt-Jakob disease and inclusion body myositis: abundant disease-associated prion protein in muscle. Ann Neurol. 2004 Jan;55(1):121-5.

LaFerla, F. M., Green, K. N. and Oddo, S. (2007). Intracellular amyloid-beta in Alzheimer's disease. Nat Rev Neurosci 8, 499-509.

Liewluck, T, et al, Mutation analysis of the GNE gene in distal myopathy with rimmed vacuoles (DMRV) patients in Thailand, Muscle Nerve 34: 775-778, 2006.

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Nonaka, I.; Sunohara, N.; Ishiura, S.; Satoyoshi, E. Familial distal myopathy with rimmed vacuole and lamellar (myeloid) body formation. J. Neurol. Sci. 51: 141-155, 1981.

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Mail Bill: btillier@shaw.ca