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Rheumatology E-learning
University of Szeged
Department of Rheumatology and Immunology
Introduction
Idiopathic inflammatory myopathies (IIM) are
a group of systemic diseases characterized
by an immune mediated attack on skeletal
muscle
Characterized by
○ Proximal muscle weakness
○ Nonsuppurative inflammation of skeletal muscle
○ Accompanied by extramuscular manifestations
Is it a myopathy or neuropathy?
Both muscle diseases and nerve diseases may present with weakness or pain.
Neuropathic processes tend to be: Asymmetrical
Distal > proximal
Usually accompanied by sensory abnormalities(paraesthesia, hypaesthesia)
Myopathic processes tend to be: Symmetrical
Proximal > distal
How to differentiate between
proximal and distal weakness?
Proximal weakness
If the patient has difficulty
rising from a chair (hip
muscles) or combing his or
her hair (shoulder girdle)
Distal weakness
If the patient has difficulty
standing on his or her toes
(gastrocnemius/soleus) or
doing fine work with the
hands (intrinsics)
Is it a myopathy or myositis?
Both may present with weakness or pain.
Myopathy: E.g. familial muscular dystrophies, hypothyreosis, statin adverse
effect, etc.
Usually less rapidly progressive
Family history may be positive
No laboratory signs of muscle cell destruction (e.g. creatine-kinase (CK), lactate dehydrogenase (LDH) elevation
Myositis: Usually rapidly progressive (severe symptoms within a few days
to several weeks)
CK and LDH are markedly elevated
Other autoimmune phenomena (dermatitis, Raynaud’sphenomenon, interstitial lung disease, arthritis) may be present
The spectrum of myositis (inflammatory
myopathy)
Polymyositis (PM)
Dermatomyositis (DM)
Inclusion body myositis (IBM)
Cancer-associated myositis
Juvenile dermatomyositis
Demographics
Idiopathic inflammatory myopathies
Prevalence rates of 1:100.000
Female:Male 2:1
Peak age range in adults is 40-50 years
Polymyositis is rare in childhood,
dermatomyositis is common
Inclusion body myositis: males after the age
of 50
Immunopathogenesis
DM: Complement mediated vasculopathy
cellular infiltrate is located in the perifascicular
regions and is often perivascular
PM: Directed T cell muscle injury
cellular infiltrate is found predominantly within the
fascicle, where there are increased numbers of
cytoxic T-cells
Clinical Features
PM/DM are typically of subacute onset
Characterized by
Initially myalgia/soreness
Progressive, symmetric and usually painless proximal muscle weakness
Weakness is most severe in the pelvic girdle and shoulder girdle
Facial muscles innervated by the cranial nervesand distal muscles of the hands are spared
Major symptoms of muscle weakness
Difficulty raising the head when supine
Weakness of neck flexors with difficulty holding the head up “dropped head”
Difficulty arising from the lying position –patients become bedridden
Difficulty lifting carrying, placing items on a shelf
Difficulty climbing stairs
Impaired ability to arise from a seat – knee extensors more affected than flexors
The gait will be swaying
Complications
Interstitial lung disease 10% of cases – may be acute alveolitis or chronic progressivefibrosing alveolitis respiratory failure may also result from diaphragmatic and chest muscle weakness both can result in rapid respiratory failure and death
Esophageal disease weakness of the striated muscle of the upper 1/3 of the esophagus and/or oropharyngeal muscles can lead to nasal regurgitation, dysphagia leads to increased incidence of bacterial pneumonia, aspiration, death or malnutrition
Myocarditis
Malignancy – see cancer-associated myositis
Cutaneous manifestations of DM
Rash usually present on sun exposed parts
Gottron’s papules
Symmetric, palpable, “heaped up” appearing
erythematous eruptions overlying the MCP/IP joints of
the fingers
Heliotrope rash
Violaceous/erythematous discoloration of the upper
eyelids with peri-orbital edema
V sign or shawl sign – macular erythema over
lower neck and upper chest in a V distribution
anteriorly
Clinical Manifestations
Skin Findings
Gottron’s
Sign:
Scaly,
symmetric
eruption over
the MCP and
interphalangeal
joints
Dermatomyositis – shawl sign
Dermatomyositis – heliotropic rash
Shawl Sign
Clinical Manifestations
Skin Findings
Mechanic’s Hands:
Roughening and cracking of skin of the tips and lateral aspects of the fingers, resulting in irregular, dirty-appearing lines
Articular manifestations
Arthralgia in 25% of patients
Morning stiffness is common
Non-deforming symmetrical arthritis of
hands, wrist, feet and ankles
Occurs early in the disease and responds to
treatment of the underlying muscle disease
Interstitial Lung Disease
Screening for ILD should be included in the
initial investigation of PM/DM patients
Chest X-Ray
Pulmonary function test
○ Restrictive ventilatory defect with decreased
diffusion capacity
High-resolution lung CT
Broncho-alveolar lavage and lung biopsy if –
rarely – indicated
Interstitial Lung Disease
Histological correlation of HRCT findings
Ground glass pattern
○ prominent interstitial infiltration by inflammatory
cells without major distortion of the alveolar
architecture
○ Indicates progressive interstitial lung disease
Reticular opacities
○ fibrosis in association with gross distortion of
alveolar structures
○ Indicates non progression of lung disease
Interstitial Lung Disease
Clinical manifestations
Asymptomatic
Cough
Dyspnea on exertion
Bibasilar inspiratory crepitations
Dispnea at rest
Respiratory failure
ILD is considered to be a major risk factor for premature death in patients with myositis
Inclusion Body Myositis
Recognized as the most common acquired muscle disease in those older than 50 yrs of age
Muscle weakness develops insidiously
Asymmetric pattern of muscle involvement
Weakness and atrophy are first observed in the quadriceps muscles Frequent falls
But distal muscles are more often involved than inPM/DM Early involvement of the long finger flexors
Inability to grip the examiners fingers
Foot drop due to peroneus muscle weakness
DM/PM and Malignancy –
Cancer-associated myositis There is a six-fold increase in the risk of malignancy in
DM and two-fold increase risk in PM
Factors that increase the probability of an associated malignancy Patients over the age of 50yrs
Refractory disease
Acute onset of disease and recurrence of disease
Elevated ESR
Female sex
In every patient, especially in those with high risk, cancer screening must be performed at diagnosisand even in the following few years if there is indication
Diagnosis
Criteria proposed by Bohan and Peter in 19751. Symmetric proximal muscle weakness by physical
exam
2. Elevation of serum skeletal muscle enzymes –CPK, Aldolase, AST, ALT, LDH
3. EMG triad short, small, polyphasic motor unit action potentials
Fibrillations – positive sharp waves and insertional irritability
bizarre high frequency repetitive discharges
4. Muscle degeneration, regeneration, necrosis, phagocytosis and interstitial mononuclear infiltrateon biopsy
5. Typical skin rash of DM
Muscle Enzymes
Muscle enzymes are elevated ASAT, ALAT, LDH, CPK
CPK most sensitive and best measure of muscle injury CPK can be elevated as much as 50 fold in PM/DM CPK elevation more than 100 fold should call the
diagnosis into question, and would rather suggestrhabdomyolysis
Rising CPK level may be the first indication of disease reactivation, even before muscle weakness develops
ALAT and ASAT also increase – in many cases, they aremistakenly regarded as a sign of liver disease! If ALAT and ASAT are increased, and muscle weakness is present - perform CPK testing instead of unnecessaryhepatic work-up!
Electromyography
EMG findings are not specific for IIM, but help in thedistinction from 1) neuropathic origin, and 2) from non-inflammatory myopathies
1) Myopathic motor unit action potentials Polyphasic
Short duration
Low amplitude
2) Evidence of increased membrane irritability Positive sharp waves
Fibrillation potentials
Complex repetitive discharges
Muscle Biopsy
Definitive diagnostic procedure and should be performed prior to treatment
Open biopsy is preferable to needle biopsy
Site of biopsy Vastus lateralis, biceps brachii or deltoid muscle
Avoid atrophic muscles or muscle on which EMG has been performed
Tissue obtained should be sent for Conventional light microscopy
Immunohistochemical studies – dystrophies
Electron microscopy
Due to patchy nature of histological changes the biopsy may be normal or inconclusive
Close collaboration between clinician and pathologist
Polymyositis: CD8+Tcells, endomysial infiltration
Dermatomyositis: Humoral response B cells, CD4+ T cells; perifascicular/perivascular infiltration
Lymphocytic infiltration with muscle
necrosis
Histology: DM
Skin Biopsy
Direct immunofluorescencestudy of a skin lesion from a patient with dermatomyositis
Intense staining of immunoglobulins along the dermal-epidermal junction
Biopsy was taken from a dermatomyositis patient with the cutaneous finding of flagellate erythema
Inclusion body myositis -
pathology Key features of IBM
Congo red positive amyloid deposits
Rimmed vacuoles
EM – whorled membranous material and tubulofilamentous inclusions
The inflammatory cells invade non-vacuolated fibers, while the vacuolated fibers are not invaded by T cells.
Two independent processes Primary T cell driven immune process identical to PM
Degenerative process in which B-amyloid and related proteins participate in vacuolar degeneration
Autoantibodies in IIM
Classified as
Myositis-associated antibodies (anti-Ro/SSA, anti-U1RNP) – found in other autoimmunediseases too
Myositis-specific antibodies
Myositis specific antibodies Anti-synthetase antibodies: autoantibodies to
aminoacyl-tRNA synthetases (e.g. anti-Jo1)
Anti-Mi-2 ( anti helicase )
Anti SRP ( signal recognition particle)
What is anti-synthetase syndrome?
•It is a subcategory of the inflammatory myositisdefined by the presence of autoantibodies to aminoacyl-tRNA synthetases (20%). •Specific clinical manifestations: ILD, arthritis, Raynaud's phenomenon, fever, and mechanic’s hands. •Steroid-dependent disease – frequent relapsesduring the tapering of corticosteroids – otherimmunosuppressants are required•Worse prognosis
Differential Diagnosis
Muscular dystrophies Limb-girdle muscular dystrophy
Dysferlinopathy ( Miyoshi myopathy)
Dystrophinapathy – Duchene muscular dystrophy
Metabolic myopathies Lipid and glycogen storage disorders
Mitochondrial myopathies
Endocrine myopathies Hypo/Hyperthyroidism
Cushing syndrome
Hypo/Hyperparathyroidism
Acromegaly
Drug induced myositis D-penicillamine, Quinidine, Procainamide, IFN alpha, IL-2
HMG CoA reductase inhibitors – noninflammatory, necrotizing myopathy
Therapy
Treatment of IIM has traditionally relied upon
the use of corticosteroids and
immunosuppressive agents
Treatment causes generalized
immunosuppression and is not organ or
antigen specific
Corticosteroids
Remains the first line treatment of choice
60% to 70% response rate
Starting dose – oral prednisone 1mg/kg for 4 to 6 weeks then taper by 5 mg per week
Combination with a steroid sparing agent such as methotrexate/azathioprine is associated with a lower relapse rate and a better long term outcome
Pulse IV methylprednisolone Patients with severe myositis
ILD
GI angiopathy
Steroid resistant disease
20%-30% of cases response is slow or incomplete
Methotrexate and azathioprine have both been shown to be effective
Combination of Methotrexate and Azathioprine have a synergistic effect
For the more difficult cases Intravenous immunoglobulin
Cyclophosphamide
Mycophenolate Mofetil
Rituximab (anti-CD20 – B-cell depleting antibody)
Recommended