Inflammatory myopathies Flashcards
What is the evidence of immune mechanisms in polymysitis and dermatomyositis?
- Presence of inflammation on biopsy
- Association wtih other autoimmune disease (ex. Type 1 diabetes)
- Production of autoantibodies (ANA, AntiRNP, etc)
- Production of myositis specific antibodies (anti-Jo-1, anti-Mi-2)
Polymyositis and Dermatomyositis
Symptoms?
Onset?
Physican findings?
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
Epidemiology of PM/DM
Its very rare
Women:Men = 2:1
African America > Caucasians
Peak age is 30-50 years
What are the HLA asociations of Polyositis and Dermatomyositis?
HLA-B8, HLADR3, HLA DRW 52
What conditions are associated with polymyolitis and dermatomyolitis?
Interstitial lung disease
Raynaud’s
Non erosive symmetric inflammatory polyarthritis
Other autoimmune disease
MALIGNANCY MORE FREQUENTLY ASSOCIATED WITH DERMATOMYOLITIS
What muscle enzymes are significant in polymyositis and dermatomyositis, and what do they show
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
What autoantibodies are seen in dermatomyositis and polymositis?
80% of cases have elevated Anti-Nuclear Antibody (ANA)
Presence of ANA may reflect overlap syndrome
- Anti RNP - mixed connective tissue disease
- Anti Scl 70 - Scleroderma
Myositis specific antibodies (MSA) in about 30% of patients with both PM and DM
What are the three major categories of Myositis specific antibodies? Important!
- Anti-aminoacyl t-RNA synthetases –> ubiquitously expressed
- Antibodies to signal recognition particle
- Antibodies to Mi-2 (a nuclear helicase)
Anti-aminoacyl-tRNA synthetases
Where are they expressed?
What do they do?
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
What is anti-synthetase syndrome?
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
Anti-Mi 2 antibodies
In which condition are they found
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
Anti signal recognizing particle antibody (Anti-SRP)
Its 4% of dermatomyositis and polymyositis
Severe and rapidly progressive weakness
dysphagia
very high CK’s
Initial steroid response
Necrotic/regenerating fibers without inflammation
Anti-155/140
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
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?
Dermatomyositis has the most risk for cancer
Pts are susceptible to adenocarcinoma
Risk is greatest in patients greater than 60 years
How does dermatomyositis differ from polymyositis?
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
What is Amyopathic dermatomyositis?
This is a variant of dermatomyositis
It has no weakness or abnormal enzymes for two years
What do you see on H&E and immunoflourescence in dermatomyositis?
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
Inclusion body myolitis
Onset?
M/F?
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
What are the clinical features of Inclusion Body Myositis?
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
Inclusion body myositis lab values?
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
What are the characteristics of Inclusion body myositis on EMG/NCV?
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
What is the treatment for polymyositis and dermatomyositis?
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
Treatment of inclusion body myositis?
Modest if there is any response to corticosteroid or immunosuppresive agents
What are the three idiopathic causes of inflammation of the muscle?
Polymyositis
Dermatomyositis
Inclusion body myositis
Define:
Endomysium
Perimysium
Epimysium
Endomysium - surrounds a single muscle fiber
Perimysium - divides muscle into fascicles
Epimysium - surrounds the entire muscle
What are the two key features of myopathic injury to muscle
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
What is the pathogenesis/pathology of polymyositis?
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
Dermatopathology pathology and pathogenesis?
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
Inclusion body myositis pathology and pathogenesis?
Etiologic agent?
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
