Inflammatory myopathies

Question 1

What is the evidence of immune mechanisms in polymysitis and dermatomyositis?

Answer 1

1. Presence of inflammation on biopsy
2. Association wtih other autoimmune disease (ex. Type 1 diabetes)
3. Production of autoantibodies (ANA, AntiRNP, etc)
4. Production of myositis specific antibodies (anti-Jo-1, anti-Mi-2)

Question 2

Polymyositis and Dermatomyositis

Symptoms?

Onset?

Physican findings?

Answer 2

Symptoms - painful muscle weakness. Specific muscle groups can be affected like striated muscle of the esophogus causing dysphasia

Onset - weeks to months

Physical - proximal muscle weakness (hip, shoulder girdle) +/- muscle tenderness

Question 3

Epidemiology of PM/DM

Answer 3

Its very rare

Women:Men = 2:1

African America > Caucasians

Peak age is 30-50 years

Question 4

What are the HLA asociations of Polyositis and Dermatomyositis?

Answer 4

HLA-B8, HLADR3, HLA DRW 52

Question 5

What conditions are associated with polymyolitis and dermatomyolitis?

Answer 5

Interstitial lung disease

Raynaud’s

Non erosive symmetric inflammatory polyarthritis

Other autoimmune disease

MALIGNANCY MORE FREQUENTLY ASSOCIATED WITH DERMATOMYOLITIS

Question 6

What muscle enzymes are significant in polymyositis and dermatomyositis, and what do they show

Answer 6

CK-MM >> CK MB but CK MB fraction may be high in PM/DM due to increased expression of CK beta chain in inflammed skeletal muscle, increased beta chain fraction in regenerating msucle

ALT, AST and LDH are less muscle specific but can be elevated in PM and DM

Question 7

What autoantibodies are seen in dermatomyositis and polymositis?

Answer 7

80% of cases have elevated Anti-Nuclear Antibody (ANA)

Presence of ANA may reflect overlap syndrome

1. Anti RNP - mixed connective tissue disease
2. Anti Scl 70 - Scleroderma

Myositis specific antibodies (MSA) in about 30% of patients with both PM and DM

Question 8

What are the three major categories of Myositis specific antibodies? Important!

Answer 8

1. Anti-aminoacyl t-RNA synthetases –> ubiquitously expressed
2. Antibodies to signal recognition particle
3. Antibodies to Mi-2 (a nuclear helicase)

Question 9

Anti-aminoacyl-tRNA synthetases

Where are they expressed?

What do they do?

Answer 9

Its a ubiquitously expressed cytoplasmic enzymes

The catalyze esterification of a specific AA to its cognate tRNA to form an aminoacyl tRNA

Unique tRNA for each of the 20 AA’s

They are mutually exclusive - meaning that usually one anti-MSA per patient

Big example is Anti-Jo-1 (its the most common anti-histadyl t-RNA synthetase; an example of an anti-aminoacyl-tRNA synthetases

Question 10

What is anti-synthetase syndrome?

Answer 10

This is a condition described with all anti-synthetases antibodies. The phenotypes vary. The include:

• myositis (90%)
• Interstitial lung disease (ILD) - 30% without MSA, 50-75% with anti-Jo, 95% wtih anti-PL12
• nonerosive arthritis
• “mechanic’s hands
• Raynaud’s

Question 11

Anti-Mi 2 antibodies

In which condition are they found

Answer 11

Found in patients with dermatomyositis. Presence in polymyositis is dependant on test

Patient with this antibodies get sicker but are quick to recover so it has a favorable prognosis.

Patients with this antibody are less likely to develop malignancies than other patients with dermatomyolitis

Question 12

Anti signal recognizing particle antibody (Anti-SRP)

Answer 12

Its 4% of dermatomyositis and polymyositis

Severe and rapidly progressive weakness

dysphagia

very high CK’s

Initial steroid response

Necrotic/regenerating fibers without inflammation

Question 13

Anti-155/140

Answer 13

Its a dermatomyositis and cancer associated muscle specifc antibody

highly specific for DM

Antigen unknown

Patients with this antibody have an increased risk of malignancy

Question 14

The risk of malignancy is higher in dermatomyositis or polymyositis?

What type of cancer are these patients at most risk for?

Which population is at most risk of this malignancy?

Answer 14

Dermatomyositis has the most risk for cancer

Pts are susceptible to adenocarcinoma

Risk is greatest in patients greater than 60 years

Question 15

How does dermatomyositis differ from polymyositis?

Answer 15

The specific rash in dermatomyositis is like that seen in lupus - it is descried as a “Heliotrope” rash (violeceous to dusky periorbital rash)

Gottren’s papules are also noticed - these are slightly elevated violaceous papules

The rash precedes (40% of the time), is concurrent, or occurs after onset of myositis

Rash is usually in photosensitive areas

But also there is a non specific rash:

Shawl sign - rash on the nect and upper chest. Also alopecia (loss of hair)

Patients are pruritic

Scalp scaliness and/or hair loss

Question 16

What is Amyopathic dermatomyositis?

Answer 16

This is a variant of dermatomyositis

It has no weakness or abnormal enzymes for two years

Question 17

What do you see on H&E and immunoflourescence in dermatomyositis?

Answer 17

H&E - vacuolated basal cells. Scattered lymphocytes in the underlying dermis and clusters of lymphocytes around the superficial vessels

Immunoflourescence - deposition of complement proteins and immunoglobulin at the dermal-epidermal similar to lupus. However, Key difference is that in DM it is immunoglobulin deposition opposed to complement in lupus

Question 18

Inclusion body myolitis

Onset?

M/F?

Answer 18

Generally starts after 50

Most common idiopathic myopathy but still rare

Along with sarcopenia, most common myopathy in the elderly

Accounts for up to 30% of inlamatory myopathies

Males>>Females

Question 19

What are the clinical features of Inclusion Body Myositis?

Answer 19

Insidous onset

delayed diagnosis

Assymetric involvement

Early weakness/atrophy –> mostly distal

Dysphagia - because or esophageal/pharyngeal invovlemtn

mild facial weakness

Few if any sensory probles

Reflexes normal to slighlty decrased

Unusually associated wtih autoimmune disease like SLE, Sjogren’s, scleroderma, sarcoid

Question 20

Inclusion body myositis lab values?

Answer 20

Modestly elevated CK’s

ANA positive in some pts

Muscle specific antibodies negative

Monoclonal gammopathy in up to 20%

Significant incidence of HLA DR3 phenotype

Question 21

What are the characteristics of Inclusion body myositis on EMG/NCV?

Answer 21

Up to 30% of patients on nerve conduction studies have evidence of a mild axonal sensory neuropathy.

EMG demonstrates increased spontaneous and insertional activity, small polyphasic motor unit action potentials (MUAPs) and early recruitment

In addition, large polyphasic MUAPs can also be demonstrated in one-third of patients that has led to the misinterpretation of a neurogenic process and misdiagnosis of amyotrophic lateral sclerosis (ALS) in some patients.

However, large polyphasic MUAPs can also be seen in myopathies (ie, PM, DM, muscular dystrophies) and probably reflects the chronicity of the disease process rather than a neurogenic etiology

Question 22

What is the treatment for polymyositis and dermatomyositis?

Answer 22

Corticosteroids

Treat underlying if present

Methotrexate and azthioprine

IV gammaglobulin for sever life threatening disease

Cyclophosphomide, cyclosporin, mycophenolate and others for refractory disaese

Rituxamab, anti-TNF’s

Question 23

Treatment of inclusion body myositis?

Answer 23

Modest if there is any response to corticosteroid or immunosuppresive agents

Question 24

What are the three idiopathic causes of inflammation of the muscle?

Answer 24

Polymyositis

Dermatomyositis

Inclusion body myositis

Question 25

Define:

Endomysium

Perimysium

Epimysium

Answer 25

Endomysium - surrounds a single muscle fiber

Perimysium - divides muscle into fascicles

Epimysium - surrounds the entire muscle

Question 26

What are the two key features of myopathic injury to muscle

Answer 26

segmental necrosis and regeration

• Phagocytosis of necrotic muscle fiber
• Regeneration fiber with basophilic

General RULE: if oyu see purple in muscle its a sign of regeneration

Question 27

What is the pathogenesis/pathology of polymyositis?

Answer 27

mature lymphocytes deep in the muscle within the endomysium

Necrotic and regeneration fibers that are scattered randomly throughout the muscle

There is also a cell mediated response against muscle fibers –> cytotoxic T cells and macrophages

Question 28

Dermatopathology pathology and pathogenesis?

Answer 28

There is perivascular inflammation in epimysium and perimysium

Perifascicular atrophy, necrosis and regeneration

Deposition of C5b-9 membrane attack complex in endomysial capillaries

Pathogenesis:

• Primary microvascular injurry –> MAC
• Inapropriate intracellular production of type 1 interferon-induciable molecules –> endothilial and perifascicular myofiber injury

Question 29

Inclusion body myositis pathology and pathogenesis?

Etiologic agent?

Answer 29

Inflammation of muscle fiber injury just like in polymyositis - 1) Cytotoxic T cells in endomysium
and 2) necrosis and regeneration of muscle fibers

Regenerative changes in muscle fibers from abnormal transcription and folding of alien proteins like beta amyloid (TRIIM):

• Tubular filaments (EM)
• Rimmed vacuoles
• Intracellular amyloid deposits
• Immunoreactivity for “alien” proteins (eg beta amyloid)
• Mitochondrial alterations

Etiologic agent can be - virus, toxin, aging