Dermatomyositis

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DERMATOMYOSITIS CASE7 A 52-year-old woman presents with the chief complaint of a 6-month history of progressive muscle weakness and a skin rash. In particular, she has noticed increased difficulty in climbing stairs and getting out of a chair. She has also had more difficulty raising items to high shelves, and lately she has even had problems keeping her arms raised while combing her hair. Symptoms have not been accompanied by myalgias. In addition, she has noted a 10-lb weight loss. Physical examination is remarkable for a diffuse purple/red discoloration of the skin over her cheeks, nose, and eyelids, and extending to her chest. Examination also confirms the proximal muscle weakness. Laboratory findings show an increase in the following: creatine kinase (CK, 10X normal), aspartate aminotransferase (AST), and alanine aminotransferase (ALT). Myoglobin is positive in the urine. Serology shows no anti-DNA antibodies but is positive for anti-Jo-1 antibodies. SALIENT FEATURES PRIMARY DIAGNOSIS PATHOPHYSIOLOGY In most cases, the cause of an inflammatory myopathy is unclear. For some reason, the body’s immune system turns against its own muscles and damages muscle tissue in an autoimmune process. The exact cause of Dermatomyositis is still not clear. However, researchers have found similarities between this disease and autoimmune disorders. Autoimmune diseases occurs when the body’s disease fighting cells or antibodies attack healthy body cells which leads to compromise immune system. In DM, these cells attack the small blood vessels that supply muscles and skin. Viral infections are also believed to contribute to this disease.

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DERMATOMYOSITIS

CASE7

A 52-year-old  woman presents  with   the  chief  complaint  of  a  6-month  history  of  progressive muscle weakness and a skin rash. In particular, she has noticed increased difficulty in climbing stairs and getting out of a chair. She has also had more difficulty raising items to high shelves, and lately she has even had problems keeping her arms raised while combing her hair. Symptoms have not been accompanied by myalgias. In addition, she has noted a 10-lb weight loss.

Physical examination is remarkable for a diffuse purple/red discoloration of the skin over her cheeks, nose, and eyelids, and extending to her chest. Examination also confirms the proximal muscle weakness.

Laboratory  findings show an   increase   in   the   following:   creatine   kinase   (CK,   10X  normal),   aspartate aminotransferase (AST), and alanine aminotransferase (ALT). Myoglobin is positive in the urine. Serology shows no anti-DNA antibodies but is positive for anti-Jo-1 antibodies.

SALIENT FEATURES

PRIMARY DIAGNOSIS

PATHOPHYSIOLOGY

In most cases, the cause of an inflammatory myopathy is unclear. For some reason, the body’s immune system turns against its own muscles and damages muscle tissue in an autoimmune process. 

The exact   cause  of  Dermatomyositis   is   still  not   clear.  However,   researchers  have   found similarities between this disease and autoimmune disorders. Autoimmune diseases occurs when the body’s disease fighting cells or antibodies attack healthy body cells which leads to compromise immune system. In DM, these cells attack the small blood vessels that supply muscles and skin. Viral infections are also believed to contribute to this disease.

The disease starts when putative antibodies or other factors activate C3. Activated C3 leads to formation of C3b, C3bNEO and membrane attack complex (MAC), which are deposited in and around endothelial cell wall of the endomysial capillaries. Deposition of MAC leads to destruction of capillaries, ischemia, or microinfarcts, most prominent in the fascicles, and perifascicular atrophy. B cells, plasmacytoid dendritic cells, CD4 T cells, and MACROPHAGES traffic from the circulation to the muscle. Endothelial expression of vascular cell  adhesion molecule (VCAM) and intercellular adhesion molecule (ICAM) is induced by cytokines released by mononuclear cells. Integrins, specifically very late  activation antigen (VLA)-4 and lymphocyte   function-associated   antigen   (LFA)-1,   bind   VCAM   and   ICAM   and   promote   T   cell   and macrophage infiltration of muscle through endothelial cell wall.

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MANAGEMENT

Therapy   for  dermatomyositis   involves  both  general  measures  and  specific  measures   to   control   the muscle disease and the skin disease. In addition, some patients with dermatomyositis need treatment for other systemic manifestations or complications.

The muscle component is treated by administering corticosteroids, typically with an immunosuppressive agent.   The   skin   disease   is   treated   by   avoiding   sun   exposure   and   by   using   sunscreens   and photoprotective   clothing,   as   well   as   with   topical   corticosteroids,   antimalarial   agents,   and immunomodulatory   medications   such   as   methotrexate,   mycophenolatemofetil,   or   intravenous immunoglobulin.

Surgical care is usually unnecessary in the management of dermatomyositis. Some patients may benefit from surgical removal of focal areas of calcinosis, particularly those that are painful. Inpatient care is needed for patients with fulminant dermatomyositis with muscle and/or internal organ involvement.

Children and adolescents are much more prone to the development of calcinosis. Aggressive and early treatment may prevent this complication.

TREATMENT AND PROGNOSIS

The   prognosis   for   patients   with   dermatomyositis   and   polymyositiswas   poor   before   the   use   of corticosteroids,  with mortality rates as high as 50% or more. Corticosteroids remain the first-line of treatment for polymyositis and dermatomyositis. Immunosuppressive drugs are used in steroid-resistant disease   or   as   steroid-sparing   agents   and   include   azathioprine   and   methotrexate.   Intravenous immunoglobulin (IVIG), cyclophosphamide, cyclosporine, and rituximab (an antibody that targets B cells) are   third-linetherapies.   Inclusion   body   myositis   usually   responds   poorly   to   steroids   or 

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immunosuppressive therapies, another feature that argues against an inflammatory or immune origin for this disorder.

Now there are numerous treatments and immunomodulatory drugs.  According to published data in 2012   (based   on   a   study   of   random  adult   dermatomyositis   and   polymyositis   patients   seen   at   the University of Michigan from 1997 to 2003) the survival rates for dermatomyositis were 70% at 5 years and 57% at 10 years.Thus,   it   is   important that treatment begin as soon as possible.  The cutaneous manifestations   of   dermatomyositis   may   or   may   not   improve   with   therapy   in   parallel   with   the improvement of the myositis. In some patients the weakness and rash resolve together. In others, the two are not linked, with one or the other being more challenging to control. Often, cutaneous disease persists after adequate control of the muscle disease.

LEARNING OBJECTIVES

1. Genetic, nongenetic and immunologic factors in the Etiology of SLE

Genetic Factors

Family  members  of  patients  have  an   increased   risk  of  developing  SLE.  As  many  as  20% of clinically   unaffected   first-degree   relatives   of   SLE   patients   reveal   autoantibodies   and   other immunoregulatory abnormalities.

There   is   a   higher   rate   of   concordance   (>20%)   in  monozygotic   twins  when   compared  with dizygotic twins (1% to 3%).

Studies   of   HLA   associations   support   the   concept   that  MHC   genes   regulate   production   of particular   autoantibodies.   Specific   alleles   of   the  HLA-DQ locus   have   been   linked   to   the production of anti–double stranded DNA, anti-Sm, and antiphospholipid antibodies, although the relative risk is small.

Some lupus patients have inherited deficiencies of early complement components, such as C2, C4, or C1q. Lack of complement may impair removal of circulating immune complexes by the mononuclear phagocyte system, thus favoring tissue deposition. Knockout mice lacking C4 or certain   complement   receptors   are   also   prone   to   develop   lupus-like   autoimmunity.   Various mechanisms have been invoked, including failure to clear immune complexes and loss of B-cell self-tolerance. It has also been proposed that deficiency of C1q results in defective phagocytic clearance of apoptotic cells. Many cells normally undergo apoptosis, and if they are not cleared their nuclear components may elicit immune responses.

Genome-wide association studies have identified several genetic loci that may be associated with   the disease.  Many of   these   loci  encode proteins   involved  in   lymphocyte  signaling  and interferon responses, both of which may play a role in lupus pathogenesis, as   discussed later. The relative risk for each locus is small, and even taken together these loci account for 20% or less of the genetic predisposition, suggesting an important role for environmental factors.

Immunologic Factors

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Failure of self-tolerance in B cells results from defective elimination of self-reactive B cells in the bone marrow or defects in peripheral tolerance mechanisms.

CD4+ helper T cells specific for nucleosomal antigens also escape tolerance and contribute to the   production  of   high-affinity   pathogenic   autoantibodies.   The   autoantibodies   in   SLE   show characteristics   of   T   cell-dependent   antibodies   produced   in   germinal   centers,   and   increased numbers of follicular helper T cells have been detected in the blood of SLE patients.

Type I interferons play a role in lymphocyte activation in SLE. High levels of circulating type I interferons and a molecular signature in blood cells suggesting exposure to these cytokines has been   reported   in   SLE  patients   and   correlates  with  disease   severity.   Type   I   interferons   are antiviral cytokines that are normally produced during innate immune responses to viruses. It may  be   that   nucleic   acids   engage  TLRs  on  dendritic   cells   and   stimulate   the  production  of interferons.   In   other   words,   self   nucleic   acids   mimic   their   microbial   counterparts.   How interferons   contribute   to   the  development  of   SLE   is  unclear;   these   cytokines  may  activate dendritic cells and B cells and promote TH1 responses, all of which may stimulate the production of pathogenic autoantibodies.

TLR engagement  by  nuclear  DNA and RNA contained  in   immune complexes  may activate  B lymphocytes. These TLRs function normally to sense microbial products, including nucleic acids. Thus,   B   cells   specific   for   nuclear   antigens  may   get   second   signals   from  TLRs   and  may  be activated, resulting in increased production of antinuclear autoantibodies.

Other cytokines that may play a role  in unregulated B-cell  activation include the TNF family member   BAFF,  which   promotes   survival   of   B   cells.   In   some   patients   and   animal  models, increased production of BAFF has been reported, prompting attempts to block the cytokine or its receptor as therapy for SLE.

Environmental Factors

Exposure to ultraviolet (UV) light exacerbates the disease in many individuals. UV irradiation may   induce   apoptosis   in   cells   and   may   alter   the   DNA   in   such   a   way   that   it   becomes immunogenic,  perhaps  because  of  enhanced recognition by TLRs.   In  addition,  UV  light  may modulate the immune response, for example, by stimulating keratinocytes to produce IL-1, a cytokine known to promote inflammation.

The gender bias of SLE is partly attributable to actions of sex hormones and partly related to genes on the X chromosome, independent of hormone effects.

Drugssuch as hydralazine, procainamide, and D-penicillamine can induce an SLE-like response in humans.

2. Criteria for the Diagnosis of SLE

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3. Common manifestations of lupus

4. Role of ANA and Immune complexes in the pathogenesis of renal disease in SLE

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5. What is lupus anticoagulant and what clinical and laboratory features noted in patients who have this antibody?

SLE patients may have coagulation disorders that are often features of an anti-phospholipid antibody syndrome. Antibodies found in this syndrome may lead to prolongation of activated partial thromboplastin time ( aPTT). Lupus anticoagulant can be demonstrated in the blood of these patients.

6. Briefly describe the pathology in the joints, CNS, serosal surface, Heart, and Lung.

Joint symptoms, including arthralgia and arthritis

Serosalsurface , inflammation especially pericarditis and pleuritis

Heart, endocarditis of the characteristic atypical nonbacterial verrucous( Libman-Sacks) form, in which vegetations are seen on both sides of the mitral valve leaflet, the tricuspid valve is less frequently involved.

Lungs. Diffuse interstitial pulmonary fibrosis, manifest as interstitial pneumonitis or diffuse fibrosingalveolitis.

7. What is the long term prognosis of LE?

Renal failure and infections are the most common cause of death in patients with SLE 

8. Describe chronic discoid LE, subacute cutaneous LE, and drug-induced LE

Discoid lupus is a chronic skin disease characterized by well-demarcated, erythematous discoid plaques, typically on the face and scalp but without systemic (extracutaneous ) symptoms.

Antibodies to double-stranded DNA are typically absent.There is a 5-10% risk of systemic disease (SLE)

Drug-induced LE. ANA test may become positive and typical symptoms of SLE may develop following administration of a variety of drugs ( hydrazine for hypertension) symptoms typically disappear after discontinuation of the drug. Drug-induced LE differs from SLE in that 

It is not associated with antibodies to double-stranded DNAAntibodies to histones are present in 95% of affected people.Renal involvement is rare.Genetic susceptibility is indicated by a frequent association with HLA-DR4

LABORATORY DIAGNOSIS OF CONNECTIVE TISSUE DISEASES

1. Describe   the   four   ANA   patterns,   including   the   significance   of   the   nuclear   and centromere patterns. What is the importance of DNA and SM antibodies in the diagnosis of  SLE? How is  serum levels  of  complement affected in SLE? What  is  the cause and 

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significance of low serum complement levels in SLE? What is the sensitivity of U1-RNP antibodies for mixed connective tissue disease (MCTD)?

The  pattern  of   the  ANA  test   can  give   information  about   the   type  of  autoimmune  disease present and the appropriate treatment program. A homogenous (diffuse) pattern appears as total nuclear fluorescence and is common in people with systemic lupus. A peripheral pattern indicates that fluorescence occurs at the edges of the nucleus  in a shaggy appearance; this pattern is almost exclusive to systemic lupus. A speckled pattern is also found in lupus. Another pattern, known as a nucleolar pattern, is common in people with scleroderma.

Homogenous   (diffuse)—associated  with SLE,  mixed  connective  tissue  disease,  and drug-

induced lupus

Speckled—associated with SLE, Sjögren syndrome, scleroderma, polymyositis, rheumatoid 

arthritis, and mixed connective tissue disease

Nucleolar—associated with scleroderma and polymyositis

Centromere   pattern   (peripheral)—associated   with   scleroderma   and   CREST   (Calcinosis, 

Raynaud syndrome, Esophogeal dysmotility, Sclerodactyly, Telangiectasia)

Complement   levels  may   be   decreased   due   to   increased   consumption   or,  more   rarely,   a 

hereditary deficiency. Hereditary deficiency in one of the complement proteins will usually lead 

to a high frequency of recurrent microbial infections. Decreased complement levels also are 

associated with an increased risk of developing an autoimmune disease. Both C3 and C4 levels 

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are   typically   depressed   inSLE while   C3   alone   is   low   in septicemia and   infections   caused 

by fungi or parasites such   as malaria.   If   the   deficiency   is   due   to   an 

underlying acute or chronic condition,  complement  levels  will  usually  return to normal  if   the 

underlying condition can be resolved.

Anti-dsDNA Antibody

The anti-double-stranded DNA antibody (anti-dsDNA) is a specific type of ANA antibody found 

in  about  30% of  people  with systemic   lupus.  Less  than 1% of  healthy   individuals  have this 

antibody, making it helpful in confirming a diagnosis of systemic lupus. [The absence of anti-

dsDNA, however, does not exclude a diagnosis of lupus.] The presence of anti-dsDNA antibodies 

often suggests more serious lupus, such as lupus nephritis (kidney lupus). When the disease is 

active,  especially   in   the  kidneys,  high  amounts  of  anti-DNA antibodies  are  usually  present. 

However, the anti-dsDNA test cannot be used to monitor lupus activity, because anti-dsDNA 

can be present without any clinical activity. Three tests are currently used to detect anti-dsDNA 

antibodies,   namely   enzyme-linked   immunosorbent   assay   (ELISA),   the   Crithidia   luciliae 

immunofluorescence test, and a test called radioimmunoassay.

Anti-Smith Antibody

An   antibody   to   Sm,   a   ribonucleoprotein   found   in   the   nucleus   of   a   cell,   is   found   almost 

exclusively in people with lupus. It is present in 20% of people with the disease (although the 

incidence varies among different ethnic groups),  but  it   is  rarely found in people with other 

rheumatic diseases and its incidence in healthy individuals is less than 1%. Therefore, it can also 

be helpful  in confirming a diagnosis of systemic lupus. Unlike anti-dsDNA, anti-Sm does not 

correlate with the presence of kidney lupus. Prospective studies have been performed as to 

whether anti-Sm correlates with lupus flares and disease activity, although evidence seems to 

suggests that it does not. The anti-Sm antibody is usually measured by one of four methods: 

ELISA, counterimmunoelectrophoreses (CIE), immunodiffusion, or hemagglutination.

Anti-U1RNP Antibody

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Anti-U1RNP antibodies are commonly found along with anti-Sm antibodies in people with SLE. 

The incidence of anti-U1RNP antibodies in people with lupus is approximately 25%, while less 

than 1% of healthy individuals possess this antibody. However, unlike anti-dsDNA and anti-Sm 

antibodies, anti-U1RNP antibodies are not specific to lupus; they can be found in other 

rheumatic conditions, including rheumatoid arthritis, systemic sclerosis, Sjogren’s syndrome, 

and polymyositis. 

Anti-U1RNP has shown to be associated with features of scleroderma, including Raynaud’s 

phenomenon; it has also been linked to other conditions, such as Jaccoud’s arthropathy, a 

deformity of the hand caused by arthritis. Levels of anti-U1RNP may fluctuate in individuals 

over time, but this fluctuation has not proven to be a significant indicator of disease activity.

2. Select and interpret the appropriate antibody and complement test for SLE, rheumatoid arthritis, scleroderma, inflammatory myopathies, and Sjorgren’s syndrom.

3. Define rheumatoid factor (RF). What is the stimulus for RF production? How specific is this test for rheumatoid arthritis?

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Rheumatoid   factor (RF)   is   the autoantibody (antibody directed   against   an   organism's   own tissues)   that   was   first   found   in rheumatoid   arthritis.   It   is   defined   as   an antibody against the Fc portion of IgG (an antibody against an antibody). These are produced when autoreactive B cells escape the natural tolerization process.

Autoantibodies   specific   for   the   Fc  portion  of   IgG  are   known  as   rheumatoid   factors   (RFs)3 because of their common occurrence in patients with rheumatoid arthritis (RA). RFs also can be detected in up to 30% of normal individuals, but these RFs are of low affinity and low titer and do not have any pathological significance. In contrast, high-affinity RFs found in RA patients can form immune complexes, activate complement, and augment local inflammatory reactions

4. List the diseases associated with the depression of complement (c3, c4, or both) and indicate the changes in c4 and c3 associated with each of these diseases.

Decreased complement activity may be seen with:

Recurrent microbial infections (usually bacterial) – c3 alone is decreased

Autoimmune diseases, including SLE and rheumatoid arthritis –both c3 and c4

Hereditary angioedema – low cerum level of c4

Cirrhosis   - c4 concentration reduced

Hepatitis    – decreased specific c4 activity without c3 inclusion

INFLAMMATROY MYOPATHIES

List the most common organs affected, the pathologic findings in affected tissues, and the clinical manifestations of the three subsets of inflammatory myopathies.

Inflammatory   myopathies   comprise   an   uncommon,   heterogeneous   group   of   disorders characterized by injury and inflammation of mainly the  skeletal muscles, which are probably immunologically   mediated.   Three  distinct disorders, dermatomyositis, polymyositis, and inclusion-bodymyositis,  are  included  in  this  category.  These may occur  alone or with other immune-mediated diseases, particularly systemic sclerosis.

A. DermatomyositisIt is a systemic autoimmune disease that typically presents with proximal muscle weakness and skin changes.Pathogenesis: It is an immunologic disease in which damage to small blood vessels contributes to muscle injury. The vasculopathic changes can beseen as telangiectasias(dilated capillary loops) in the nailfolds, eyelids, and gums, and as dropout of capillaryvessels in skeletal 

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muscle.   Biopsies   of  muscle   and   skin  mayshow   deposition   of   the   complement  membrane attackcomplex (C5b-9) within capillary beds in both tissues. Aninflammatory signature enriched for genes that are upregulatedby type I  interferons is seen in muscle and in  leukocytes.The prominence of this signature appears to correlatewith disease activity. Various autoantibodies are often detected by serologic studies, and B lymphocytes as wellas plasma cells are part of the   inflammatory   infiltrate   thatis   seen   in   muscles.   Certain   autoantibodies   tend   to   be associatedwith specific clinical features:• Anti-Mi2 antibodies ,Anti-Jo1 , Anti-P155/P140 antibodies

Morphology:Muscle biopsies of affected patients show infiltrates of mononuclear inflammatory cells that tend to be most pronounced in the perimysial connective tissue and around blood vessels. Sometimes there is a distinctive pattern in which myofiber atrophy is accentuated at the   edges   of   the   fascicles—  perifascicular atrophy (See   picture:   Dermatomyositis   below). Segmental fiber necrosis and regeneration may also be seen. Immunohistochemicalstudies may identify an infiltrate rich in CD4+ T-helper cells and the deposition of C5b-9 in capillary vessels. Electron microscopic studies may show tubuloreticular endothelial cell inclusions, a feature of a number of inflammatory disorders that are linked to a type I interferon response.

Clinical Features:Muscle  weakness   is   slow  in  onset,   symmetric,  and  often accompanied  by myalgias. It typically affects the proximal muscles first. As a result, tasks such as getting up from a chair and climbing steps become increasingly difficult. Fine movements controlled by distal muscles   are   affected   only   late   in   the   disease.   Associated   myopathic   changes   on electrophysiologic studies and elevation in serum creatinekinase levels are reflective of muscle damage. Various rashes are described in dermatomyositis, but the most characteristic ones are a   lilac   colored   discoloration   of   the   upper   eyelids  (heliotrope rash) associated   with periorbitaledema (See picture: Dermatomyositis) and a scaling erythematous eruption or dusky red patches over the knuckles, elbows, and knees (Gottron papules). Dysphagia resulting from involvement  of  oropharyngeal  and  esophageal  muscles  occurs   in  one   third  of   the  affected individuals, and another 10% of patients have interstitial lung disease, which can sometimes be rapidly  progressive  and  lead  to death.  Cardiac   involvement   is  common,  but  rarely   leads  to cardiac failure.

B. Polymyositis

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It   is   an   adult-onset   inflammatory   myopathy   that   shares   myalgia   and   weakness   with dermatomyositisbut lacks its distinctive cutaneous features  and is thereforeto some degree a diagnosis   of   exclusion.   As   in   dermatomyositis,patients   typically   develop   symmetric proximalmuscle involvement, and there may be inflammatoryinvolvement of the heart and the lungs, as well as similarautoantibodies.

Pathogenesis:The  pathogenesis   of   polymyositis   is   uncertain,   but   it   is   believed   to  have   an immunologic basis. CD8- positive cytotoxic T cells are a prominent part of the inflammatory infiltrate in affected muscle, and it is hypothesized that these cells are the mediators of tissue damage.   Unlike   dermatomyositis,   vascular   injury   is   not   believed   tohave   a  major   role   in polymyositis.

Morphology:     Mononuclear   inflammatory   cell   infiltrates   are   present,   but   in   contrast   to dermatomyositis,   these   are   usually   endomysial   in   location.   Sometimes   myofibers   with otherwise   normal  morphology   appear   to   be   invaded   by  mononuclear   inflammatory   cells. Degenerating necrotic, regenerating, and atrophic myofibersare typically found in a random or patchy   distribution.   The   perifascicularpattern   of   atrophy   that   is   characteristic   of dermatomyositisis absent.

C. Inclusion body myositisIs a disease of late adulthood that typically affects patients older than 50 years and is the most common inflammatory myopathy in patients older than age 65 years.Most affected individuals presentwith slowly progressive muscle weakness that tends tobe most severe in the quadriceps and   the  distal   upperextremity  muscles.  Dysphagia   from  esophageal   and  pharyngealmuscle involvement   is  not  uncommon.   Laboratorystudies  usually   show modestly  elevated  creatine kinaselevels; most myositis-associated autoantibodies are absent,although an antibody to cN1A has recently been described.

Morphology: Inclusion body myositis has a number of features that are similar to those found in polymyositis, including:

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• Patchy often endomysial mononuclear inflammatory cell infiltrates rich in CD8+ T-cells• Increased sarcolemmal expression of MHC class I antigens• Focal invasion of normal appearing myofibers by inflammatory cells• Admixed degenerating and regenerating myofibers

Other associated changes, however, are more typical or even specific for inclusion body myositis, as follows:• Abnormal cytoplasmic inclusions described as “rimmed vacuoles”• Tubolofilamentous inclusions in myofibers, seen by electronmicroscopiy•   Cytoplasmic   inclusions   containing   proteins   typically   associated   with   neurodegenerative diseases, like beta-amyloid, TDP-43, and ubiquitin• Endomysial fibrosis and fatty replacement, reflective of a chronic disease course

It has certain features in common with polymyositis, as discussed earlier. On the other hand, it shares   some  features  with  neurodegenerative  diseases,   such  as   the  presence  of  abnormal protein aggregates. Furthermore, there are several familial inclusion body myopathies that are also associated with chronic myopathic changes and rimmed vacuoles. These typically lack any associated   inflammation—   hence   the   designation  inclusion body “myopathy” rather   than “myositis.”