Idiopathic Inflammatory
Myopathies (IIM)
• Chronic inflammation of striated
muscle (myositis)
• Characteristic cutaneous
features
• Variety of systemic
complications
●The characteristic “heliotrope” rash of
dermatomyositis was first described in 1875
(Paris).
● Eleven years later Wagner coined the term
polymyositis (PM)
●Gottron, in 1930, reported on the skin lesions
of dermatomyositis .
●1975, Bohan and Peter proposed five criteria
or the diagnosis of PM and DM that are still
used today
Epidemiology
Prevalence of DM and PM ~ 1/100,000
• The overall incidence of IIM ranges from 2
to 10 new cases per million persons at risk
per year
• The prevalence of IBM in Western Australia
is high
Prevalence of IBM:
5-10/million (in> 50 y/o: 1-3/100,000)
• IIM can occur at any age, includes both
childhood and adult peaks.
• The mean age of myositis onset is
increased when there is an associated
malignancy.
• The overall female-to-male incidence ratio
is 2.5:1.
• This ratio is lower(nearly 1:1) in childhood
disease and with malignancy.
• (10:1)when there is a coexisting
connective tissue disease.
Association with other disorders
• PM-DM occurs in overlap with SSc more
than any other CTD.
• Often associated with one of several
serum autoantibodes such as anti-U1RNP, anti-PM-Scl, or anti-U3-RNP.
Environmental factors
• Disease onset is more frequent in the winter
and spring months, especially in childhood
cases
• Disease relapses were noted most
frequently during summer months, perhaps
precipitated by infection or sun exposure.
• DM and PM have occurred in HIV-infected
patients
• Myositis occurs in GVHD.
Genetic and Environmental Risk Factors
Genetic
• Reports of familial occurrence
• Higher incidence of other autoimmune disorders in first
degree relatives
• HLA DRB1
• DR3 in Anti Jo-1 Ab
Environmental Risk Factors
•
•
•
•
Infectious Agents
Drugs
Ultraviolet radiation exposure
Other agents
Genetic factors
• (HLA-DRB1*03-DQA1*05-DQB1*02), are
important risk factors (anti-synthetase,
antibody-positive patients)
• JDM associated with HLA-DQA1*0501.
• Single nucleotide polymorphism have
identified associations in genes outside the
MHC area.
• Genes regulating cytokines and their
receptors including PTPN22, interleukin (IL)1,and tumor necrosis factor (TNF)-a appear
to play a role in the development and course
of both childhood and adult onset myositis.
Idiopathic Inflammatory Myopathies
• Polymyositis (PM)
• Dermatomyositis (DM)
• Inclusion body myositis (IBM)
Clinical manifestations
‫شروع تدریجی درعرض ‪ 6-3‬ماه‬
‫گرفتاری شدید کمربند شانه ایی ولگنی‬
‫گرفتاری گردن در ‪ 50‬درصد مواقع‬
‫عدم گرفتاری چشم وصورت‬
‫گرفتاری عضالت دیستال ناشایع است‬
‫دیسفاژی ودیستونی داریم‬
‫در بچه ها و بالغان جوان شروع ممکن است سریعتر و با درد‬
‫عضالنی همراه باشد‬
‫آتروفی در موارد شدید و طول کشیده‬
‫گرفتری دیافراگم می تواند باعث نارسایی تنفسی شود‬
• Other early findings included pitting
edema of the extremities or eyelids as a
combined result of hypoalbuminemia
• Capillary leakage, and lack of muscle
tone needed to promote central venous
return.
• Pharyngeal muscle weakness may
contribute to hoarseness, dysphagia,
nasal regurgitation of liquids, or
aspiration pneumonia.
• Ventilatory muscle weakness may
contribute to dyspnea
• Unlike muscle weakness, which is a
hallmark of PM-DM, muscle
hypertrophy is more characteristic of
muscular dystrophy.
• Muscle atrophy and joint
contractures are sequelae of disease
damage; they are therefore late
findings
Constitutional
• Fatigue is a prominent complaint and it
may persist even after adequate
treatment of myositis.
• Fever is more commonly observed with
JDM, and anti-synthetase syndrome.
• Weight loss may occur in myositis
patients, but if persistent and severe,
associated malignancy should be
considered.
Skin findings in DM
• Gottron papules are scaly, erythematous
or violaceous papules, and plaques
located over bony prominences,
particularly the MTP and proximal and
DIP joints of the hands.
• Gottron sign is a macular erythema that
occursn in the same distribution. One of
these rashes is seen in 60% to 80%of
patients with DM.
• Pruritus is common,particularly in the
scalp and its presence differentiates DM
from SLE, in which pruritus is
uncommon.
Gottron's sign
symmetric, roughened, erythematous skin changes over
extensor surfaces of MCPs, IPs, elbows, and/or knees
• Heliotrope rash is purplish in
color, may be edematous or
scaling in nature, and is located
in the periorbital area, especially
over the upper eyelids
Heliotrope rash
a violaceous eruption on the upper eyelids,
sometimes with edema
Shawl sign, V sign
a diffuse flat erythema in a shawl-like distribution
or in a V-shaped pattern over the anterior neck and
chest
Erythroderma
a generalized redness
(at a variety of other skin sites: malar, forehead)
Periungual abnormalities
erythematous capillary nailbeds with vascular changes
(like other CTDs)
Abnormal loops with areas of dilatation and dropout
Calcinosis
• Soft tissue calcification, which can be
disabling, occurs most commonly in
chronic, childhood-onset DM and is less
frequent in adult-onset disease.
• Calcinosis may appear in well-controlled
myositis but more typically occurs in the
setting of chronic, active disease or aftera
prolonged delay in the initiation of
corticosteroid treatment.
• Calcinosis may be intracutaneous,
subcutaneous, fascial, or intramuscular in
location, with a predilection for sites of
repeated microtrauma (elbows, knees,
flexor surfaces of fingers, and buttocks).
• Medical therapy has been disappointing;
however,bisphosphonates have led to rapid
improvement in some cases,whereas
probenecid and infliximab have been
beneficial in othersituations.
‫تظاهرات بالینی‬
‫ریه‬
• ILD important complication in
approximately %10 of cases of DM and PM
• Respiratory failure may result from
diaphragmatic and chest wall muscle
weakness
• ILD in the inflammatory myopathies often
occurs in the context of anti-synthetase
antibodies and the anti-synthetase
syndrome
• Amyopathic patients remain at risk for
fatal ILD, malignancy,or even delayedonset, full-blown DM.
Antisynthetase (anti-Jo-1) syndrome
• ILD
• Raynaud
• Arthritis
• mechanic's hands
• Pulmonary function testing (PFT) reveals
restrictive physiology inmyositis-associated
ILD.
• NSIP and the organizing pneumonias
represent more favorable histopathology,
usual interstitial pneumonitis (UIP) and
diffuse alveolar damage (DAD) portend a
more ominous course.
• the concomitant finding of anti-Ro/SSA in
patients with anti-synthetase
autoantibodies may be associated with more
severe and progressive ILD.
• Diffuse alveolar hemorrhage with
pulmonary capillaritis is
uncommon but can be lethal.
• Pneumomediastinum, on the
other hand, is increasingly
reported.
‫تظاهرات بالینی‬
‫مری‬
• Dysphagia: Weakness of the
striated muscle of the upper onethird of the esophagus (and/or
the oropharyngeal muscles)
• more common in elderly patients
and may underlie the increased
incidence of bacterial pneumonia
‫تظاهرات بالینی‬
•
‫قلب‬
Heart failure is unusual
↑ CK-MB fraction due to involvement of
the myocardium by the myositis
Reason for ↑CK-MB levels is that the
fraction of MB is increased in
regenerating muscle
Cardiac troponin I, a more specific and
sensitive marker of cardiac damage
Conduction and ECG abnormality
Joints
• Polyarthralgias or polyarthritis, if they
occur, appear early in the disease course.
• The distribution is rheumatoid-like, and
the symptoms are relatively mild.
• Joint findings are more common with
overlap and the anti-synthetase
syndromes but are frequently in
childhood Dm.
‫‪IBM‬‬
‫گرفتاری باالی ‪ 50‬سال‬
‫شروع تدریجی وسیرکند‬
‫بروزعالیم ‪ 6-5‬سال قبل از تشخیص‬
‫میتواند غیرقرینه ” دیستال ویا فوکال باشد‬
‫میتواند تغییرات نوروپاتیک داشته باشد‬
‫می تواند باعث آتروفی عضله کوادری سپس شود‬
‫•‬
‫•‬
‫•‬
‫•‬
‫•‬
‫•‬
Immunopathogenesis
Histologic features:
• muscle fiber necrosis
• degeneration and regeneration
• inflammatory cell infiltration
Muscle Anatomy
Normal Muscle
DM
Cellular infiltrate is predominantly perifascicular and
often perivascular
B cells and plasmacytoid dendritic cells
perivascular and perimysial
inflammation
perifascicular necrosis
in DM
PM
cellular infiltrate is found predominantly within the
fascicle
cytotoxic CD8+ T cells are dominant
intense interstitial mononuclear infiltrate
with some myocyte degeneration
IBM
filamentous inclusions in electron microscopy
Rimmed vacuoles and eosinophilic muscle
An autoimmune disease
Association with other autoimmune diseases
(: Hashimoto's thyroiditis) and collagen vascular
diseases (: scleroderma)
Autoantibody response in many patients
Lymphocyte infiltration:
• B cells and plasmacytoid dendritic cells in DM
• cytotoxic CD8+ T cells
response to immunosuppressive therapies in
some patients
Dermatomyositis
Humoral immune process against
vascular endothelium
activation of complement
↓
C5b-9 deposition on endothelium
↓
capillary necrosis
↓
ischemic muscle injury
perifascicular atrophy
PM and IBM
MHC-1 expression on myocytes
Activation of CD8 T cells and lysis of
muscle fibers by release of Perforin
granules
Upregulation of cytokines, chemokines
and adhesion molecules →
↑transmigration of T cells to muscle
Initial injury
↓
muscle auto antigen release
↓
Ag presentation by
macrophages to CD4+ TH
cells
↓
Activated TH cells stimulate
macrophages (IFN-γ)
↓
inflammatory mediator
release
(: IL-1 and TNF-α)
↑expression of MHC
proteins by myocytes
↓
Auto-Ag is presented in
association with MHC-I
molecules on surface of
Myocytes
↓
destruction of myocytes by
CD8 cytotoxic T cells
Role of non-immune processes
• marked structural changes in muscle fibers in
the absence of any inflammatory cells
• lack of correlation between degree of
inflammation and degree of muscle weakness
• Some, do not respond to anti-inflammatory
therapy
• steroid treatment may eliminate inflammatory
cells but may not improve clinical disease
• disease may progress when identifiable
inflammation has subsided
Iran Study
Manifestations at onset:
muscle weakness (45%)
specific rash
(25%)
arthralgia
fever
(38%)
(16%)
myalgia
(21%)
Manifestations during the disease course:
98%:
proximal weakness
40-60%:
arthralgia, arthritis, Fever, fatigue, weight loss, myalgia, heliotrope rash
20-40%:
hair loss, dysphagia, articular rash, eyelids edema,
malar rash, pulmonary involvement, Raynaud's phenomenon
<20%:
muscular edema, cardiac manifestations, joint deformities, periungual
erythema, calcinosis
Diagnosis
clinical
laboratory
electromyography
biopsy
exclusion of other disorders with
similar features
Laboratory evaluation
Serum muscle enzyme and Abs
Serum muscle enzymes
↑in most patients
creatine kinase (CK)
[early-late, DM/IBM-PM]
lactate dehydrogenase (LDH), Aldolase
and aminotransferases
IBM: typically moderate CK↑
(< x10 normal)
Autoantibodies
Present in a majority (~ 80% of PM/DM)
ANA: ↑↑ suggest presence of another CTD
Myositis-specific autoantibodies:
• anti-histidyl-tRNA synthase (: anti-Jo-1)
• anti-signal recognition particle (anti SRP)
• anti-Mi-2
Electromyography (EMG)
evidence of muscle irritability
classic triad:
• Increased insertional activity and spontaneous
fibrillations
• Abnormal myopathic motor potential
(low amplitude, short–duration polyphasic)
• Complex repetitive discharges
Non-specific
Normal in ~ 10%
Tissue biopsies
Biopsy in DM
Skin and/or muscle biopsies may establish the
diagnosis
Skin biopsy sufficient to confirm DM if:
•
•
•
typical weakness pattern
(symmetric; proximal > distal)
+
serum muscle enzymes↑
+
classic cutaneous findings
Muscle biopsy in PM
Even in clinical scenarios highly
consistent with PM,
muscle biopsy is essential to
establishing correct diagnosis and
excluding other disorders
Open biopsy is preferred to needle
biopsy
Magnetic resonance imaging
(MRI)
Useful in:
• identify biopsy site
• longitudinal follow-up
(Tx response assessment, flares diagnosis)
Classification Criteria
• 1. Symmetrical weakness
Limb-girdle and neck flexors, with or without
dysphagia/respiratory sx
• 2. Biopsy
• 3. Elevation of muscle enzymes in serum
CK, aldolase, LDH, AST, ALT
• 4. EMG evidence
• 5. Dermatologic features
Gottron’s sign, heliotrope rash, shawl sign, etc.
Definite
Probable
Possible
Polymyositis
Dermatomyositis
4 criteria, no rash
3 criteria, no rash
2 criteria, no rash
Rash + 3 criteria
Rash + 2 criteria
Rash + 1 criteria
Differential Diagnosis
• Other myopathies
• Neuropathies
• Assosiations
(collagen-vascular disease, malignancy)
Malignancy
Can be diagnosed before, with, or after IIM diagnosis
Cancer site in 70% of cases:
cervix, lung, ovaries, pancreas, bladder, and stomach
RISK FACTORS:
DM
(especially with trunk cutaneous necrosis)
Capillary damage on muscle
biopsy
Cutaneous leukocytoclastic vasculitis
Age >65 y at diagnosis
Evaluation:
•
history, physical examination
•
Age-appropriate cancer screening tests
(: mammography and colonoscopy)
•
CT of chest, abdomen and pelvis for high risk patients
Initial therapy
• Prednisone: 1 mg/kg/day (≤ 80
mg/d)
• Severely ill patients→
methylprednisolone pulse
• taper to lowest effective dose over a
total of 9 - 12 m
Glucocorticoid-sparing agents
Initiate with GCs
First-line:
azathioprine (AZT) or methotrexate (MTX)
Response:
importance of muscle strength > muscle enzymes
Taper off GCs before tapering AZT/MTX
(careful follow-up for possibility of disease recurrence )
Resistant Disease
Consider several potential scenarios:
• Incorrect original diagnosis
• glucocorticoid-induced myopathy
• Underlying malignancy
Treatment
Rituximab
Tacrolimus
Mycophenolate mofetil
Combination therapy
Intravenous immune globulin
Cyclosporine
Cyclophosphamide
TNF inhibitors
General treatment measures
• Early physical therapy and rehabilitation
• Aspiration precautions
• DM may be photosensitive → avoid UV
• Bisphosphonate from the start of treatment
•
Sufficient Ca and Vitamin D intake
• high-dose prednisone + immunosuppressive
→ Pneumocystis jirovecii prophylaxis
Outcome Predictors:
Type of myositis
delay in diagnosis
disease severity
autoantibody profile
Response to GCs alone:
overlap myositis > DM > PM
Antisynthetase Ab:
often associated with ILD and a worse prognosis
IBM:
more resistance to treatment
Progress gradually over a period of years
By 15 y, most patients require assistance with basic daily
activities