2. Myopathy -simply refers to an abnormality of the muscle and has no other
connotation
Myositis- implies an autoimmune or infectious disorder in which the muscle histology
shows an inflammatory response
Muscular dystrophies- are genetic myopathies usually caused by a disturbance of a
structural protein or enzyme, resulting in necrosis of muscle fibres and replacement
by adipose and connective tissue
DEFINITIONS
3. • Latest definition-
• These are heterogeneous group of systemic autoimmune rheumatic disorders
characterized by chronic muscle weakness, muscle fatigue with varying degree of
involvement of other organs like skin, CVS, GI tract & lungs
4. EPIDEMIOLOGY
• Annual incidence -< 10 per million
• The incidence of the various myopathies varies according to ethnicity, age, and
gender
• The onset of PM is usually in the late teens or older: the mean patient age at onset is
50 to 60 years.
• DM shows two peaks: 5 to 15 years and 45 to 65 years.
• IBM >50 years and rare in younger adults
5. ETIOLOGY
• Genetic Risk Factors
• Polymorphisms in class I and II human leukocyte antigen (HLA) genesHLA-DRB1*0301 and
HLADQA1*050
• Polymorphisms in some non-HLA genes, such as signal transducer and activator of transcription 4
gene (STAT4) and C8orf13–BLK,
• Environmental Risk Factors
• Malignancy
6.
7. PATHOGENESIS
• Humoral Immune Response
• Cell- Mediated Immune Response
• Class 1 Major Histocompatibility Complex Expression
• Cytokines and Hypoxia
8. Humoral Immune Response
• Two types of autoantibodies
Myositis specific autoantibodies—These antibodies directed against antigens of
protein synthesis pathway and nuclear components, and are specific for myositis.
Myositis-associated autoantibodies– These antibodies are against various nuclear
and cytoplasmic antigens and are not particularly associated with any disease group
9.
10. CELL-MEDIATED IMMUNE RESPONSE
• Predominantly Perivascular–
• Seen in perimysial areas.
• Predominant cells are CD4+ T cells and macrophages.
• Usually seen in Dermatomyositis patients.
• Predominantly Endomysial–
• The inflammatory cells are primarily CD8+T cells and macrophages.
• Usually seen in Polymyositis and Inclusion Body myositis
11. Recent studies also point to a role of:
• Type 1 interferon(IFN)- inducible genes which leads to expression of MxA
and IFN-inducible gene 15 in perifascicular myofibers of Dermatomyositis
biopsies.
• Cytolytic T lymphocyte (CTLs) mediated target cell damage via perforin-
granzyme B and FasFasL pathways is seen in Polymyositis and Inclusion
Body Myositis
12. CLASS 1 MHC EXPRESSION
• In Inflammatory Myopathies there is early and widespread appearance of class 1 MHC in
non-necrotic muscle cells even in muscle cells distant from lymphocytic infiltration.
• Overexpression of Class 1MHC results in activation of NF-kB which activates both
classic(pro- inflammatory cytokines) and nonclassic(ER stress response)pathway leading to
muscle atrophy and muscle weakness
• Pro-inflammatory cytokines ↓ myogenic miRNAs(e. g., miR-1, miR-133a,miR-133b
and miR-206) and facilitate muscle degeneration
15. DERMATOMYOSITIS
• F>M
• Bimodal peaks: 5 to 15 years and 45 to 65 years.
• Symmetrical muscle involvement.
• Proximal>Distal muscle weakness.
• Myocarditis, ILD, malignancy, vasculitis, other CTDs
16. • The most specific skin manifestations are Gottron’s papules and the heliotrope rash
• Gottron’s papules are slightly elevated, violaceous, pink, or dusky red papules located
over the dorsal side of the metacarpal or interphalangeal joints. These papules may also
occur over the extensor side of the wrist, elbow, or knee joints.
• A macular rash (without papules) with the same distribution as Gottron’s papules is
called Gottron’s sign .
• The heliotrope rash is a periorbital red or violaceous erythema of one or both eyelids,
often with edema.
17. • Linear erythema overlying the extensor surfaces of joints is also relatively specific to
DM
• Photosensitive rashes, typically found on the face or scalp or over the neck (V sign),
although this rash is not specific to DM
• Another common rash in DM is located over the shoulders (shawl sign) or over the
hips (holster sign). Pruritus is common.
• Periungual erythema, nailfold telangiectasias, and cuticular overgrowth and this
development can even lead to digital ulceration.
• calcinosis
20. • Investigations
• N or ↑CK (up to 50×) others like aldolase, AST may be elevated
• MSAs (anti-MDA5, anti-TIF1, anti-Mi-2, anti-NXP2)
• Perimysial and perivascular inflammation; IFN-1 regulated proteins (MHC-1, MxA), MAC
deposition on capillaries
• CD4+ dendritic cells; B cells; macrophages
• IHC staining for myxovirus resistance proteinA(MxA) is sensitive and specific for DM.
• ANAcan be positive
• Electromyography of weak muscles shows abnormal electrical irritability, a decrease in mean
duration and amplitude of motor unit potentials with rapid firing of motor unit potentials in
relation to level of activity, these findings are nonspecific and can be seen in other
Myopathies.
21. POLYMYOSITIS
• F>M
• Mean patient age at onset is 50-60 year.
• Symmetric and proximal muscle weakness
• No skin changes
• Myocarditis, ILD, other CTDs
22. • Investigations
• Increased CK up to 50×
• Endomysial and perivascular inflammation; ubiquitous expression of MHC-1
• CD8+ T cells; macrophages; plasma cells
• EMG of weak muscles shows abnormal electrical irritability, a decrease in mean
duration and amplitude of motor unit potentials with rapid firing of motor unit
potentials in relation to level of activity,
23.
24. Ultrasonography:
• Newer usg techniques utilize contrast agents to quantify skeletal
muscle perfusion.
• Ultrasound contrast agents contain gaseous microbubbles of
about 1-5 mm in size that are intravenously injected and remain
intravascular.
• Contrast-enhanced power doppler used to examine muscle
perfusion showed inflammatory hypervascularization in patients
of dermatomyositis and polymyositis.
• Patients with oedema like changes in MRI but normal muscle
perfusion
were found to not have myositis.
• Useful in detecting calcific myonecrosis.
25. MRI:
• MRI has emerged as the method of choice to efficiently visualize
and quantify inflammation, fat infiltration,calcification and
alteration in muscle sizes.
• On MRI, muscles with inflammatory oedema are
hyperintense(white)on T2-weighted images.
• MRI also enables better guiding for interventions, such as
biopsies in areas of active disease.
26. Magnetic resonance Spectroscopy
• In myositis patients, the maximum rate of mitochondrialATP
production was half of that found in normal individuals.
• Proton spectroscopy can measure the degree of intracellular
acidification.
• Using proton MR spectroscopy, the intramyocellular pH
recovery after exercise was found to be significantly lower in
patients of myositis.
27. Blood oxygenation level-dependent Imaging
• Blood oxygenation level dependent (BOLD) MRI imaging
evaluates microcirculation functionally.
• BOLD is useful in detection of arterial insufficiency in skeletal
muscles and may serve in distinguishing vasculitis from myositis.
28. PET Scan
• 18-FDG PET reveals diffuse proximal muscle
hypermetabolism.
• In dermatomyositis patients additional advantage is
simultaneous detection of malignancies.
29. IMMUNE-MEDIATED NECROTIZING MYOPATHY
• Onset : acute to insidious
• Symmetric
• Proximal>distal
• Dysphagia,dysarthria
• Underlying CTD or malignancy or idiopathic
• Two forms
• Anti HMGCR
• Anti SRP
30. • Anti HMGCR –
– Mimic limb girdle dystrophy
– Can occur in children and young adults
– Statin exposure
– Statin naïve type wont improve with discontinuation of statins
• Anti SRP –
– Subacute
– Aggressive
– Refractory course
31. Two distinct forms of Immune Mediated Necrotizing Myopathy are:
• Investigations
• Ck – >10x
• Antibodies
• EMG- ↑ insertional and spontaneous activity with myotonic discharges
• Imaging- non specific
• Prognosis is bad
32. Characteristic findings on muscle biopsy includes multifocal necrotic and regenerating
muscle fibers without significant inflammatory infiltrates.
33. ANTISYNTHETASE SYNDROME
Clinical Features include:
• Myositis
• ILD
• Non erosive symmetrical
polyarthritis of small joints
• Raynaud’s phenomenon
• Mechanic hands
• Fever
• Some pts erythematous rash
• ILD common
34. • Investigations
• Ck ↑
• Antibodies – aminoacyl t RNAsynthetase antibody- anti Jo1
• HRCT – honeycoombing
• Imaging- non specific
• Biopsy – perimysial damage >DM
• No ↑ risk of malignancy
35. INCLUSION BODY MYOSITIS
• 50 years
• M>f
• Asymmetric, slowly progressive muscle weakness
• predilection for wrist and finger flexors and quadriceps
• Dysphagia
• No ↑ risk of malignancy
• Less responsive to therapy
36. • CK –N or only slightly elevated
• Abnormal large granular lymphocytes on flow cytometry
• Reduced ratio of CD4 to CD8 cells.
• EMG demonstrates large amplitude, long duration motor unit potentials.
• Muscle MRI- Predilection for involvement of flexor digitorum profundus in arms and
vastus medialis and lateralis muscles with sparing of rectus femoris muscle.
37. • Autoantibody targetting cytosolic 5’nucleotidase 1A(cN-1A)
antibody which is highly specific for Inclusion Body Myositis is
being used for diagnosis seen in 1/3 to 2/3 pts
• Muscle biopsy demonstrates endomysial infiltrates predominantly
CD8+ T cells and macrophages.
The inclusions contain beta sheet misfolded protein (amyloid)
which Is difficult to appreciate with congo red stain.
A New imnunostaining for p62 appears to be most sensitive for
detection of inclusions.
38.
39. MYOSITISASSOCIATED WITH MALIGNANCIES
• Dermatomyositis (20%-30%) than for Polymyositis (10%-15%).
• Patients with Dermatomyositis should be screened for tumors at the time
of diagnosis and relapse.
• Malignancy varies from hematological such as lymphoma to solid tumors such as lung,
ovary, breast and colon.
• Two mysoitis specific autoantibodies highly associated with Dermatomyositis
and malignancy in adults are-
Anti-TIF1
Anti-NXP2
Patients with these antibodies are considered high risk and screening is done aggressively.
40. COVID-19 Associated myopathy
• Symptoms include muscle weakness which is proximal more
than distal,fever,myalgias without any typical skin rash or nail
bed changes.
• Positive RTPCR for SARS-COV-2 RNA and elevated CK
• Muscle biopsy shows mild perivascular inflammation without
necrosis.
• IHC analysis showing abnormal expression of MHC class 1
antigen on and myxovirus resistance proteinAbut no evidence of
SARS-COV-2 on muscle.
41. APPROACH
• The first goal in approaching a patient with a suspected muscle disease is to determine
the correct site of the lesion.
• The second goal is to determine the cause of the myopathy
• The third goal is to determine whether a specific treatment is available and if not, to
optimally manage the patient’s symptoms to maximize functional abilities and
enhance quality of life
43. • Which negative and/or positive symptoms and signs does the
patient demonstrate
• Negative
– Weakness
– Fatigue
– Exercise intolerance
– Muscle atrophy
• Positive
– Myalgia
– Cramps
– Contractures
– myotonia
44. 1. Weakness: MOST COMMON
a) Proximal lower extremities:
• difficulty climbing stairs, arising from a low chair or toilet, or getting up
from a squatted position.
b) Proximal upper extremities:
• trouble lifting objects over their head and brushing their hair.
c) Distal upper extremities:
• difficulty opening jars, inability to turn a key in the ignition.
d) Distal lower extremities:
• tripping due to foot-drop.
e) Cranial muscle weakness:
• dysarthria, dysphagia, or ptosis.
45. 2. Fatigue
• less useful negative symptom
• Nonspecific
• abnormal fatigability after exercise can result from certain metabolic and mitochondrial
myopathies, and it is important to define the duration and intensity of exercise that provokes the
fatigue
3. Myalgia
• nonspecific symptom
• episodic (metabolic myopathies)
• constant (inflammatory muscle disorders)
• more likely to be due to orthopedic or rheumatological disorders
46. 4. Muscle cramp
• They are typically benign, occurring frequently in normal individuals, and are seldom
a feature of a primary myopathy
5. Muscle contractures
• uncommon
• They are typically provoked by exercise in patients with glycolytic enzyme
defects.
• Contractures differ from cramps in that they usually last longer and are
electrically silent with needle EMG.
• Cramps are characterized by rapidly firing motor unit discharge on needle
EMG.
47. 6. Myotonia : phenomenon of impaired relaxation of muscle after forceful
voluntary contraction.
• due to repetitive depolarization of the muscle membrane.
• Patients may complain of muscle stiffness or tightness resulting in difficulty
releasing their handgrip after a handshake, unscrewing a bottle top, or opening
their eyelids if they forcefully shut their eyes.
• Most commonly involves the hands and eyelids.
• Myotonia classically improves with repeated exercise
52. • Distal Myopathies
– Late adult-onset distalmyopathy type 1 (Welander)
– Late adult-onset distal myopathy type 2 (Markesbery/Udd)
– Early adult-onset distal myopathy type 1 (Nonaka)
– Early adult-onset distal myopathy type 2 (Miyoshi)
– Early adult-onset distal myopathy type 3 (Laing)
– Desmin myopathy
– Childhood-onset distal myopathy
• Myotonic Dystrophy
• Inflammatory Myopathies
• Inclusion Body Myositis
• Metabolic Myopathies
– Debrancher deficiency
– Acid-maltase deficiency
• Congenital Myopathies
– Nemaline myopathy
– Central core myopathy
– Centronuclear myopathy
53. • Myopathies with proximal arm/distal leg involvement
(scapuloperoneal)
• Scapuloperoneal dystrophy,
• Emery-Dreifuss dystrophy,
• LGMD1B, LGMD2A, LGMD2C–2F,
• Congenital myopathies,
• Nemaline myopathy
• Central core myopathy
• acid maltase deficiency.
• When this pattern is associated with facial weakness-
• >(FSHD)
54. DIAGNOSTIC CRITERIA
The European Alliance of
associations for
rheumatology/American
College of Rheumatology
described the classification
criteria for juvenile and adult
idiopathic inflammatory
myopathies in 2017.
55. Classification
Muscle biospy not
available
Muscle biospy available
Probable IIM 5.5-7.4 6.7-8.6
Definite IIM >7.4 > 8.6
Patients with a score in range of definite idiopathic inflammatory myopathy has a probability of
>90% for the disease
59. How to differentiate Steroid myopathy from Relapse:
▶ Features suggesting steroid myopathy include-
1. Development of weakness when on higher dose of steroid.
2. Normal serum creatine kinase levels.
3. Absence of muscle membrane irritability on EMG.
4. Other clinical features of steroid excess like moon facies, buffalo
hump.
▶ Relapse is characterized by-
1. Development of weakness while tapering prednisolone.
2. High CK levels
3. Abnormal spontaneous activity on EMG.
60. TREATMENT
Recommended treatment is based on combination of
pharmacological therapy and Non pharmacological treatment.
1. Pharmacological treatment-
▶ High dose glucocorticoids i.e., prednisone 1 mg/kg/ day is
considered the first line treatment and then gradual tapering
over 4-6 months to <10 mg/day.
▶ Second line agents include methotrexate, azathioprine,
mycophenolate, rituximab, IVIG.
61. Second line agents:
INDICATIONS:
1. Other organ system involvement (e.g. ILD, Myocarditis).
2. Increased complications of steroids like osteoporosis,
diabetes.
3. Relapse during prednisone therapy.
62. Methotrexate
• Second line agent of choice.
• Start at 7.5 mg once weekly orally and gradually increase
upto 25mg/week.
• All patients are advised folinic acid.
• Side effects include hepatotoxicity,pulmonary fibrosis (avoided in
ILD patients), infertility, leucopenia, alopecia, gastric irritation,
teratogenicity.
63. Azathioprine
• Recommended initial dose is 50 mg/day which can be increased by
50 mg every 2 weeks (maximum dose 2-3 mg/kg/day).
• Practical limitation is 6-18 months of treatment is required before
benefit can be seen.
• Thiopurine methyltransferase (TPMT) deficient patients can
present with severe bone marrow toxicity.
• Side effects include flu like illness, hepatotoxicity, pancreatitis,
leucopenia,
teratogenicity.
64. Cyclophosphamide
• Dose is 1.5-2 mg/kg/day oral.
• Side effects include bone marrow suppression, infertility,
hemorrhagic cystitis, alopecia, infections, teratogenecity.
65. Mycophenolate Mofetil
• Inhibits proliferation of T and B lymphocytes by blocking purine
synthesis.
• Second line treatment of choice for myositis patients with ILD.
• Starting dose is 1gm BD and can be increased upto 3gm/day.
• Adverse effects include bone marrow suppression, HTN,
diarrhoea, nausea, vomiting, headache, sinusitis.
• Does not cause renal or hepatotoxicity which is an advantage over
other drugs.
66. Cyclosporine
• Given at 4-6 mg/kg/day in two divided doses
• Side effects include hepatotoxicity, nephrotoxicity, HTN, hirsutism, gum
hyperplasia.
IVIG
• Used in patients refractory to prednisone and at least one second line drug.
• Treatment of choice even as monotherapy in anti-HMGCR myopathy.
• Dose is 2 gm/kg over 2-5 days then 1 gm/kg every 4-8 weeks.
• Adverse effects are hypotension, arrythmia, flushing, nephrotoxicity, aseptic
meningitis.
67. Rituximab
• Monoclonal antibody against CD20 B cells.
• Beneficial in patients refractory to steroid and at least one
second line drug.
• Dose is 750mg/square meter IV infusion with second infusion two
weeks apart.
• Maintenance dose is repeated every 6-18 months.
• Adverse effects include infusion reactions, infection, progressive
multifocal leukoencephalopathy.
69. • Non-Pharmacological treatment:
• Previouslypatients with myositis were advised against exercise because of the concerns
over possible muscle damage and inflammation.
• Recent publications have demonstrated that combining exercise with
immunosuppressive therapy is a safe approach and is beneficial.
• The exercise regimen should be individualized and supervised starting
approximately 4 weeks after initiation of immunosuppression.
70. Disease Activity and Outcome
• Muscle Examination
• Manual Muscle Test - MRC scale
– Eight muscle groups tested neck flexors, shoulder abduction (deltoid middle), biceps brachii,
wrist extensors, knee extensors (quadriceps), dorsiflexion of ankle, gluteus maximus, and gluteus
medius. The score achieved varies between 0 and 80
• Functional Index in Myositis 2
• Extramuscular Involvement
71. • The International Myositis Assessment and Clinical Studies
(IMACS)
• Improvement is based on the disease activity core set and is defined as greater than
20% improvement in three of the six variables of the core set, with two or fewer of
the variables (except the manual muscle test) worsening by less than 25%
72. • Core set
• Physician’s overall assessment of disease activity on a visual analogue scale (VAS)
• Patient’s or parent’s overall assessment of disease activity (VAS)
• Functional assessment (health assessment questionnaire)
• Muscle strength testing (manual muscle test) Serum levels of at least 2 of 4 muscle
enzymes (CK, LDH, AST, ALT) Extramuscular score (myositis disease activity
assessment VAS [MYOACT] or myositis intention to treat activity index [MITAX]),
in which disease activity in seven organ systems (general symptoms, skin, joints,
gastrointestinal tract, pulmonary, heart, and muscles) is scored
