idiopathic Inflammatory myositis

Idiopathic
Inflammatory
Myositis
DR. AMAR MBBS MD

Introduction
The inflammatory myopathies represent the largest
group of acquired and potentially treatable causes
of skeletal muscle weakness.
They are classified into three major groups:
 Polymyositis (PM)
 Dermatomyositis(DM), and
 Inclusion body myositis (IBM)

If the inflammatory changes are restricted clinically to
the striated muscles, the disease is called polymyositis
(PM)
If in addition, the skin is involved, it is called
dermatomyositis (DM),
Although the two diseases are now understood to be
immunopathologically distinct.

History
Both diseases have been known since the nineteenth
century.
Polymyositis was first described by Wagner in 1863 and
1887.
DM was established as an entity by Unverricht in a
series of articles written from 1887 to 1891.

Heinrich
Unverricht
"...it seems to me that
the skin appearance plays
such an important role in
the disease picture that
the designation
Polymyositis is not
completely accurate. In
our case, the partnership
of the skin and muscle
disease allows us to use
the elocution
Dermatomyositis...“
(translation).[

Epidemiology
The prevalence of inflammatory myopathies is
estimated at 1 in 1,00,000.
PM as a stand-alone entity is a rare disease.
DM affects both children and adults and women more
often than men
IBM is three times more frequent in men than in
women, more common in whites than blacks, and is
more likely to affect persons age > 50.

There is no internationally accepted classification system for
inflammatory myopathies.
For discussion purpose, IM’s can be classified as
i. Polymyositis
ii. Dermatomyositis
iii. Inclusion body myositis
iv. Autoimmune necrotizing myopathies
v. Myositis associated with collagen vascular disorder
vi. Myositis associated with malignancy

Polymyositis (PM)
Onset – Insidious.
Progression – Usually over a period of several
weeks or months.
Age at onset – 30-60 years of age with a small peak
at 15 years of age.
Sex – Female predominate in all age groups.

Inclusion body myositis (IBM)
In patients ≥50 years of age, IBM is the most
common of the inflammatory myopathies.
It is often misdiagnosed as PM and is suspected
only later when a patient with presumed PM does
not respond to therapy.

Aetiology & Pathogenesis
An autoimmune etiology of the inflammatory myopathies is
indirectly supported by
Association with other autoimmune or connective tissue
diseases
Presence of various autoantibodies
Association with specific major histocompatibility complex
(MHC) genes
Demonstration of T cell–mediated myocytotoxicity or
complement-mediated microangiopathy
Response to immunotherapy.

Autoantibodies and
Immunogenetics
Various autoantibodies against nuclear antigens
(antinuclear antibodies) and cytoplasmic antigens are
found in up to 30% of patients with inflammatory
myopathies.
The antibodies to cytoplasmic antigens are directed
against ribonucleoproteins involved in
i. protein synthesis (antisynthetases) (or)
ii. translational transport (anti-signal-recognition
particles).

/
Anti Jo-1
The antibody directed against the histidyl-transfer RNA
synthetase, called anti-Jo-1, accounts for 75% of all the
antisynthetases.
The clinical disorders
associated with these
antibodies usually
combine myositis with
(1) interstitial lung
disease (80%)
(2) arthritis,
(3) Raynaud syndrome,
and
(4) thickening of the skin
of the hands ("mechanic’s
hands").

Immunopathologic
Mechanisms
Dermatomyositis – Humoral Immune mechanisms.
Polymyositis & IB Myositis – T-Cell mediated immune
mechanisms.

PM & IBM - Pathogenesis
CD8 T cells, along with macrophages, initially surround
and eventually invade and destroy healthy, nonnecrotic
muscle fibers that aberrantly express class I MHC
molecules.
The CD8/MHC-I complex is characteristic of PM and IBM
and its detection can aid in confirming the histologic
diagnosis of PM.
The cytotoxic CD8 T cells contain perforin and granzyme
granules directed toward the surface of the muscle
fibers and capable of inducing myonecrosis.

Non-immune factors in IBM
In addition to the autoimmune component, there is
also a degenerative process.

Association with viral infections
Viruses including coxsackie viruses, influenza,
paramyxoviruses, mumps, cytomegalovirus, and Epstein-
Barr virus, have been indirectly associated with myositis
but studies have repeatedly failed to confirm this
association.

Role of Retroviruses
Individuals infected with HIV or with human T cell
lymphotropic virus 1 (HTLV-1) develop PM or IBM.
The inflammatory myopathy may occur as the initial
manifestation of a retroviral infection, or myositis may
develop later in the disease course.
Retroviral antigens have been detected only in
occasional endomysial macrophages and not within the
muscle fibers themselves, suggesting that persistent
infection and viral replication within the muscle does not
occur.

AZT induced myopathy
Retroviral myopathy should be distinguished from a
toxic myopathy related to long-term therapy with AZT,
characterized by fatigue, myalgia, mild muscle weakness,
and mild elevation of creatine kinase (CK).
AZT-induced myopathy, which generally improves when
the drug is discontinued, is a mitochondrial disorder
characterized histologically by “ragged-red” fibers.

Clinical Features
Usual mode of onset – Painless weakness of proximal
limb muscles, especially of hips and thighs and to a
lesser extent the shoulder, girdle and neck muscles.
The posterior and anterior neck muscles (the head may
loll) may be involved.
The pharyngeal, striated esophageal, and laryngeal
muscles (dysphagia and dysphonia) may be involved as
well.

Other muscles
In restricted forms of the disease, only the neck and the
paraspinal muscles may be implicated (camptocormia).
Distal muscles (forearm, hand, leg & foot) – Spared in
75% of cases.
Facial, Tongue and Jaw muscles – rarely affected.
Respiratory muscles slightly weakened but rarely to the
extent that causes dyspnea.

Muscles are non-tender, reflexes are usually reduced.
As the weeks and months pass, the weakness and
muscle atrophy progress unless treatment is initiated.
Without physical therapy, fibrous contracture of muscles
eventually develops.
Some elderly individuals with a particularly chronic form
of the disease may present with severe atrophy and
fibrosis of muscles.

Dermatomyositis
Muscle weakness similar to that PM but the
denominative feature is the rash.
Most often, the skin changes precede the muscle
syndrome and take the form of a localized or diffuse
erythema, maculopapular eruption, scaling eczematoid
dermatitis, or exfoliative dermatitis.
Sometimes skin and muscle changes evolve together
over a period of 3 weeks or even less.

Characteristic
skin lesion
A characteristic form
of the skin lesions
are patches of a scaly
roughness over the
extensor surfaces of
joints (elbows,
knuckles, and knees)
with varying degrees
of pink-purple
coloration.

Gottron’s
papules
Red, raised papules may
be present over exposed
surfaces such as the
elbows, knuckles, and
distal and proximal
interphalangeal joints.

Heliotrope
Rash
Lilac-colored (heliotrope)
change in the skin over
the eyelids, on the bridge
of the nose, on the
cheeks, and over the
forehead; it may have a
scaly component.

Heliotrope
rash in an
Indian patient

Shawl sign
A predominance of rash over
the neck and upper shoulders
has been termed the V sign,
while rash over the shoulders
and upper arms, the shawl
sign.
This distribution suggests
that the skin changes reflect
heightened photosensitivity

Mechanic’s
hands
Cracking of the finger
pad skin, commonly
involving the first,
second, and third
fingers

DM - Other Physical Findings
Periarticular and subcutaneous calcifications.
Raynaud phenomenon in almost 1/3rd of patients.
Dilated or thrombosed nail-fold capillaries.

Extramuscular Manifestations
of DM/PM
Systemic symptoms, such as fever, malaise, weight loss,
arthralgia, and Raynaud’s phenomenon, especially when
inflammatory myopathy is associated with a connective
tissue disorder.
Joint contractures, mostly in DM and especially in
children. (related to skin thickening)
Dysphagia and gastrointestinal symptoms, due to
involvement of oropharyngeal striated muscles and
upper esophagus, especially in DM and IBM.

Cardiac disturbances, including atrioventricular
conduction defects, tachyarrhythmias, dilated
cardiomyopathy, a low ejection fraction, and congestive
heart failure, which may rarely occur either from the
disease itself or from hypertension associated with
longterm use of glucocorticoids.

Pulmonary dysfunction, due to weakness of the thoracic
muscles, interstitial lung disease, or drug-induced
pneumonitis (e.g., from methotrexate), which may cause
dyspnea, nonproductive cough, and aspiration
pneumonia.
Interstitial lung disease may precede myopathy or occur
early in the disease and develops in up to 10% of
patients with PM or DM, most of whom have antibodies
to t-RNA Synthetases.

Subcutaneous calcifications, in DM, sometimes
extruding on the skin and causing ulcerations and
infections.
Arthralgias, synovitis, or deforming arthropathy with
subluxation in the interphalangeal joints, which can
occur in some patients with DM and PM who have Jo-1
antibodies

Malignancy associated with
DM/PM
Many studies have been done to prove the association
between Malignancies and Myostitis especially PM &
DM.
The association ranging between 29-66% according to
various studies.
Commonest malignancies are Lung & Colon Cancer in
males and Breast & Ovarian Cancer in females.

Systemic autoimmune diseases
with PM/DM
In both PM and DM, the inflammatory changes are often
not confined to muscle but are associated with systemic
autoimmune diseases such as rheumatoid arthritis,
scleroderma, lupus erythematosus, or combinations
thereof (mixed connective tissue disease).

Overlap syndrome
In overlap syndromes that incorporate autoimmune
disease and myositis, there is usually greater muscular
weakness and atrophy than can be accounted for by the
muscle changes alone.
Arthritis or periarticular inflammation may limit motion
because of pain, result in disuse atrophy, and also at
times cause a vasculitic polyneuropathy, the
interpretation of diminished strength in these
autoimmune diseases is not simple.

Malaise, aches, and pains points to a systemic disease.
Sometimes the diagnosis of myositis must depend on
muscle biopsy, EMG findings, and measurements of
muscle enzymes in the serum.

Inclusion Body Myositis
In patients ≥50 years of age, IBM is the most common of
the inflammatory myopathies.
Weakness and atrophy of the distal muscles, especially
foot extensors and deep finger flexors, occur in almost
all cases of IBM and may be a clue to early diagnosis.
Most common presentation - weakness in the small
muscles of the hands, especially finger flexors, and
complain of inability to hold objects such as golf clubs or
perform tasks such as turning keys or tying knots.
Recurrent Falls – Early Quadriceps weakness.

IBM – Continued
Occasionally, the weakness and accompanying atrophy
can be asymmetric and selectively involve the
quadriceps, iliopsoas, triceps, biceps, and finger flexors,
resembling a lower motor neuron disease.
Dysphagia is common (60% of patients).
Sensory examination is normal.
Disease progression is slow but steady.

In at least 20% of cases, IBM is associated with systemic
autoimmune or connective tissue diseases.
Familial aggregation of typical IBM may occur; such
cases have been designated as familial inflammatory
IBM.

Lab Diagnosis
Creatine Kinase
Tends to be higher in Polymyositis than in
Dermatomyositis because of the widespread single
fiber necrosis in Polymyositis.
In DM, if there are infarcts, CK will be raised
moderately as well.
Usually elevated up to 5- 50 times ULN.
Elevated up to 10 times in IBM.

RA and ANA are positive in fewer than half of cases.
Other antibodies can be found on occasion that are
directed against constituents of a nucleolar protein
complex (PM-Scl) and ribonucleoproteins (Ro /SS-A
and La/SS-B).

20 percent of patients with PM and DM have antibodies
against various cellular components of muscle, in
particular, antibodies directed against cytoplasmic
transfer ribonucleic acid (tRNA) synthetases (anti-Jol), or
against the tRNA itself.
These are fairly specific to PM and, less frequently to
DM, they are found when the myositis is coupled with an
expanded illness that involves other organs or
connective tissues.

Myoglobinuria can be detected in majority of
patients with any form of myositis, particularly a
necrotizing form.

EMG
A typical Myopathic pattern is found on EMG - many
abnormally brief action potentials of low voltage in
addition to numerous fibrillation potentials, trains of
positive sharp waves, occasional polyphasic units, and
myotonic activity-all but the brief potentials possibly
reflecting irritability of the muscle membranes.
The EMG is also helpful in choosing a muscle for biopsy
sampling.

MRI
MRI can refine the distribution of all lesions and aid
in targeting the muscle biopsy.
May show abnormalities in Tl, T2 and STIR signal
intensity define regions of increased water content
and inflammation and spectroscopic studies
demonstrate regional deficits in energy production.

Muscle
Biopsy in
PM
Endomysial
inflammatory
infiltrate
surrounding and
invading non-
necrotic muscle
fibers with no
vacuolization.

Muscle
Biopsy in
DM
Perivascular and
Perifascicular
infiltrates with
perifascicular
atrophy.

Muscle
Biopsy in
IBM
Vacuolated muscle
fibers infiltrated with
CD8/MHC-1
complexes.

Differential Diagnosis
Subacute - Denervating conditions such as SMA or ALS.
Acute – Acute neuropathy such as GBS, Transverse
myelitis, or a neurotropic viral infection such as
poliomyelitis or west nile virus.
Myofascitis
Necrotizing autoimmune myositis.
Drug induced myopathies – D-Penicillamine,
procainamide and statins. AZT causes a mitochondrial
myopathy.

Management
The goal of therapy is to improve muscle strength,
thereby improving function in activities of daily
living, and ameliorate the extramuscular
manifestations (rash, dysphagia, dyspnea, fever).
The level of CK and degree of leukocyte infiltration
often reduces on treatment with glucocorticoids.
But CK levels should never be the target of therapy.

Glucocorticoids
Oral prednisone is the initial treatment of choice, the effectiveness and
side effects of this therapy determine the future need for stronger
immunosuppressive drugs.
Initial dose – 1mg/kg/day
After 3-4 weeks – Dose tapering to be started
Over 10 weeks – dose reduced to 1mg/kg alternate day
Every 3-4 weeks – Dosage reduced by 5-10 mg (until lowest possible
dose that controls the disease is achieved)

Efficacy of Glucocorticoids
Determined by an objective increase in muscle strength
and activities of daily living.
If prednisolone provides no objective benefit after 3
months of therapy, it is advisable to taper and stop the
drug so that the next in-line immunosuppressive therapy
can be started.
Almost all patients with DM/PM respond to steroids to
some degree or for some period of time.

In acute and particularly severe cases, high dose
Methylprednisolone (1gm infused over 2 hours
daily for 5 days) is used.

Steroid myopathy
The long-term use of prednisone may cause increased
weakness associated with a normal or unchanged CK
level, this effect is referred to as steroid myopathy.
In a patient who previously responded to high doses of
prednisone, the development of new weakness may be
related to steroid myopathy or to disease activity that
either will respond to a higher dose of glucocorticoids or
has become glucocorticoid-resistant.
In uncertain cases, the prednisone dosage can be
steadily increased or decreased as desired: the cause of
the weakness is usually evident in 2–8 weeks.

Other immunosuppressive
drugs
Approximately 75% of the patients ultimately require
additional treatment during the course of the illness.
Indications –
i. patient fails to respond adequately to glucocorticoids
after a 3-month trial
ii. the patient becomes glucocorticoid-resistant
iii. glucocorticoid-related side effects appear
iv. attempts to lower the prednisone dose repeatedly result
in a new relapse
v. rapidly progressive disease with evolving severe
weakness and respiratory failure develops.

Other immunosuppressive
drugs
Azathioprine – Dose up to 3mg/kg/day is used. As
effective as other drugs when used on a long term basis.
Methotrexate - Faster onset of action than
azathioprine. It is given orally starting at 7.5 mg weekly
for the first 3 weeks (2.5 mg every 12 h for 3 doses), with
gradual dose escalation by 2.5 mg per week to a total of
25 mg weekly.
A rare side effect is methotrexate pneumonitis, which
can be difficult to distinguish from the interstitial lung
disease of the primary myopathy associated with Jo-1
antibodies

Mycophenolate Mofetil – Also has a faster onset of
action than azathioprine. 2.5-3gm/day in 2 divided
doses. It is well tolerated for long term therapy.
Rituximab – Monoclonal anti-CD20 antibody
(rituximab) has been shown in a small uncontrolled
series to benefit patients with DM and PM at a
dose of intravenously 750 mg/m2, repeated in 2
weeks and sometimes required every 6 to 18
months.

Cyclophosphamide (0.5–1 g/m2 IV monthly for 6
months) has limited success and significant toxicity.
Tacrolimus (formerly known as Fk506) has been
effective in some difficult cases of PM especially
with interstitial lung disease.

Immunomodulation
In a controlled trial of patients with refractory DM, IVIg improved
not only strength and rash but also the underlying
immunopathology.
The benefit is often short-lived (≤8 weeks), and repeated
infusions every 6–8 weeks are generally required to maintain
improvement.
A dose of 2 g/kg divided over 2–5 days per course is
recommended.
Uncontrolled observations suggest that IVIg may also be
beneficial for patients with PM.
Neither plasmapheresis nor leukapheresis appears to be effective
in PM and DM.

Sequential empirical approach to
the treatment of PM and DM
High-dose
prednisone
01
Azathioprine,
Mycophenolate
or
Methotrexate
for steroid-
sparing effect
02
IVIg
03
A trial, with one of the
following agents,
chosen according to
age, degree of
disability, tolerance,
experience with the
drug, and general
health: rituximab,
cyclosporine,
cyclophosphamide or
tacrolimus.
04

Treatment strategy
A combination of prednisone in low dosage and one of
these immunosuppressant drugs.
This approach is generally necessary when myocarditis
or interstitial pneumonitis is coupled with DM.

Patients with Interstitial Lung Disease may benefit from
aggressive treatment with Cyclophosphamide (or)
Tacrolimus.

Poor Response to therapy
A patient with presumed PM who has not responded to
any form of immunotherapy most likely has IBM or
another disease, usually a metabolic myopathy, a
muscular dystrophy, a drug-induced myopathy, or an
endocrinopathy.
In these cases, a repeat muscle biopsy and a renewed
search for another cause of the myopathy is indicated.

Calcinosis - Management
Calcinosis, a manifestation of DM, is difficult to treat
however, new calcium deposits may be prevented if the
primary disease responds to the available therapies.
Bisphosphonates, aluminium hydroxide, probenecid,
colchicine, low doses of warfarin, calcium blockers, and
surgical excision have all been tried without success.

Inclusion Body Myositis -
Management
Generally resistant to immunosuppressive therapies.
Prednisolone together with azathioprine or
methotrexate is often tried for a few months in newly
diagnosed patients.
IVIg in IBM with minimal benefit in up to 30% of
patients was found in one study.
A 2- to 3-month trial with IVIg may be reasonable for
selected patients with IBM who experience rapid
progression of muscle weakness or choking episodes
due to worsening dysphagia.

Prognosis
The 5-year survival rate for treated patients with PM
and DM is ~95%, and the 10-year survival rate is 84%.
Death is usually due to pulmonary cardiac, or other
systemic complications.
The prognosis is worse for patients who are severely
affected at presentation, when initial treatment is
delayed, and in cases with severe dysphagia or
respiratory difficulties.

DM responds more favorably to therapy than PM and
thus has a better prognosis. Most patients improve with
therapy, and many make a full functional recovery, which
is often sustained with maintenance therapy.
Up to 30% may be left with some residual muscle
weakness. Relapses may occur at any time.

IBM has the least favorable prognosis of the
inflammatory myopathies.
Most patients will require the use of an assistive device
such as a cane, walker, or wheelchair within 5–10 years
of onset.
In general, the older the age of onset in IBM, the more
rapidly progressive is the course.

idiopathic Inflammatory myositis

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