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Inflammatory Myopathies

Chapter 377 | Part 11: Immune-Mediated, Inflammatory, and Rheumatologic Disorders · Part 11 – Rheumatology & Immunology · Chapter 377

Key Clinical Points

  1. Inflammatory myopathies (IMs) include dermatomyositis (DM), polymyositis (PM), immune-mediated necrotizing myopathy (IMNM), antisynthetase syndrome (ASyS), and inclusion body myositis (IBM).
  2. DM is associated with a ~15% risk of malignancy within the first 2-3 years in adults and specific MSAs like anti-Mi-2, anti-TIF1-γ, anti-MDA5, anti-NXP2, and anti-SAE.
  3. IBM is the most common cause of myopathy in adults >50 years, characterized by asymmetric weakness of finger/wrist flexors and quadriceps with poor response to immunotherapy.
  4. IMNM is associated with anti-HMGCR or anti-SRP antibodies; anti-HMGCR myopathy does not improve upon statin discontinuation.
  5. ASyS is defined by a constellation of features: myositis, nonerosive arthritis, ILD, Raynaud's, mechanic hands, and fever with anti-aminoacyl-tRNA synthetase antibodies.
  6. Creatine kinase (CK) is the most sensitive marker of muscle destruction; a level >2000 U/L is almost always indicative of myopathy.
  7. Muscle biopsy is essential to distinguish between IMs, particularly to exclude IBM in suspected PM cases.
  8. Anti-MDA5 antibodies are associated with severe skin ulcerations and rapidly progressive ILD; anti-TIF1-γ (p155) is highly specific for cancer-associated DM.
  9. Symmetric, proximal weakness is the hallmark of DM, PM, and IMNM, while IBM presents with asymmetric, often distal/proximal mixed patterns.
  10. Pulmonary involvement (ILD) is common in anti-MDA5 and ASyS; lung involvement in anti-SAE is typically milder.

DEFINITION & CLASSIFICATION

• Definition (Harrison's 22e): Inflammatory myopathies (IMs) are a group of disorders characterized by muscle inflammation and weakness. • Major Types: ◦ Dermatomyositis (DM) ◦ Polymyositis (PM) ◦ Immune-mediated necrotizing myopathy (IMNM) ◦ Antisynthetase syndrome (ASyS) ◦ Inclusion body myositis (IBM) • Other IMs: ◦ Infection-related ◦ Eosinophilic myositis ◦ Granulomatous myositis ◦ Myositis triggered by checkpoint inhibitors • Note on Overlap: Inflammatory cell infiltrates can occur in non-inflammatory conditions like muscular dystrophies, metabolic myopathies, and toxic myopathies.

EPIDEMIOLOGY

• Incidence/Prevalence: ◦ Incidence: up to 16 cases per 100,000 ◦ Prevalence: 14–32 per 100,000 • Demographics by Type: ◦ DM: Can occur in children (juvenile DM) and adults; more common in women. ◦ PM & ASyS: More common in women. ◦ IBM: Most common myopathy in adults >50 years; more common in men. • Prognostic Factors: ◦ Younger, male patients may have a worse prognosis.

ETIOLOGY & PATHOPHYSIOLOGY

Dermatomyositis (DM)

• Primary Mechanism: Driven by type I interferon (IFN)-mediated pathways, specifically IFN-β. ◦ Note: Immunoglobulin deposition on endothelial cells is largely absent; complement may be secondary. ◦ MSAs are directly pathogenic: e.g., anti-Mi-2 antibodies enter myonuclei and inhibit the CHD4/NuRD complex.

Inclusion Body Myositis (IBM)

• Mechanism: T-cell inflammation and specific autoantibodies against muscle proteins. ◦ Environment: Chronic inflammatory environment alters protein synthesis/degradation via aberrant immunoproteasome expression. ◦ Degenerative Features: Accumulation of p62 and LC3 (markers of ER stress and autophagy). ◦ TDP-43 Pathology: Extruded from myonuclei; loss of splicing repression leads to inclusion of cryptic exons and abnormal translation.

Immune-Mediated Necrotizing Myopathy (IMNM)

• Mechanism: Not fully understood; not primarily complement driven. ◦ Anti-HMGCR: May bind to sarcolemma receptors → accumulation of acetyl-CoA → increased lipids in muscle fibers. ◦ Anti-SRP: Considered directly causal to the associated IMNM.

Antisynthetase Syndrome (ASyS)

• Mechanism: Driven by gamma-IFN rather than type 1 IFN. ◦ Pathogenicity: Antibodies bind specific aminoacyl-tRNA synthetases → impaired protein synthesis.

CLINICAL FEATURES

Dermatomyositis (DM)

• Presentation: Symmetric, proximal > distal weakness with characteristic rash. ◦ Rash Types: ◦ Heliotrope: Erythematous discoloration of eyelids with periorbital edema. ◦ Gottron sign/papules: Erythematous rash over extensor surfaces (joints) and raised papules over knuckles. ◦ V-sign: Rash on sun-exposed anterior neck and chest. ◦ Shawl sign: Rash over back of neck and shoulders. ◦ Other Features: Nail bed telangiectasias, subcutaneous calcium deposits, pruritus. ◦ Spectrum: Amyopathic DM (rash only) or hypomyopathic DM (minimal muscle involvement). ◦ Malignancy Risk: ~15% in adult-onset cases within first 2–3 years. ◦ Lung Involvement: Associated with anti-MDA5 (severe) or ASyS.

Polymyositis (PM)

• Presentation: Symmetric, proximal weakness worsening over weeks to months. ◦ Complications: Potential heart, lung, and joint involvement; increased risk of cancer (though lower than DM).

Immune-Mediated Necrotizing Myopathy (IMNM)

• Presentation: Acute or insidious onset of symmetric, proximal > distal weakness. ◦ Associated Features: Dysphagia, dysarthria, myalgia. ◦ Subtypes: ◦ Anti-HMGCR: Often in patients >50; can be triggered by statins (but does not improve with discontinuation). ◦ Anti-SRP: Subacute, aggressive, and relatively refractory course.

Antisynthetase Syndrome (ASyS)

• Definition: Myositis + nonerosive arthritis + ILD + Raynaud's + mechanic hands + fever. ◦ Antibodies: Anti-aminoacyl-tRNA synthetase. ◦ Note: Some patients may present with rash and biopsy features of DM.

Inclusion Body Myositis (IBM)

• Demographics: Patients >50 years; more common in men. ◦ Presentation: Slowly progressive, asymmetric weakness; predilection for finger/wrist flexors and quadriceps. ◦ Features: Common dysphagia; no increased risk of malignancy. ◦ Progression: Mean time to wheelchair use is ~15 years.

DIFFERENTIAL DIAGNOSIS

• Localization Strategy: ◦ Cerebral/Spinal: Central symptoms or sensory deficits. ◦ Peripheral Nerve/NMJ: Fatigue (Myasthenia Gravis) or specific nerve patterns. ◦ Neurogenic: Atrophy with fasciculations (e.g., ALS). ◦ Muscular Dystrophy: Scapular winging, calf hypertrophy, early contractures, positive family history. • Laboratory Differentiation: ◦ CK > 2000 U/L → almost always a myopathy. ◦ Slightly elevated CK → may be neurogenic. ◦ Normal Lab Workup + symptoms → Fibromyalgia. ◦ Elevated ESR/CRP + normal CK/EMG → Polymyalgia rheumatica. • Clinical Markers: ◦ Heliotrope + Gottron papules + dilated nailfold capillaries → DM. ◦ Finger flexor weakness + quadriceps involvement in >50 years → IBM.

DIAGNOSTIC APPROACH

  1. Clinical Assessment: Determine site of lesion (central, peripheral, or muscle) and identify patterns (e.g., symmetric vs asymmetric, proximal vs distal).
  2. Laboratory Testing: ◦ CK: Measure for sensitivity to muscle destruction; >2000 U/L indicates myopathy. ◦ Aldolase: May be elevated in 10% of cases with normal CK. ◦ ANA: Non-specific finding.
  3. Myositis-Specific Antibodies (MSAs): ◦ Anti-Mi-2: 15–20% of DM; associated with florid rash and good prognosis. ◦ Anti-MDA5: 10–20% of DM; associated with palmar rash, ulcerations, and rapid ILD. ◦ Anti-TIF1-γ (p155): 89% specificity for cancer-associated DM. ◦ Anti-NXP-2: Associated with calcinosis, subcutaneous edema, and dysphagia. ◦ Anti-SAE: Associated with cancer in 14–57%; mild ILD.
  4. Electrophysiology: ◦ EMG/NCS: Used to localize the site of lesion; EMG guides biopsy selection.
  5. Imaging: ◦ MRI (STIR): Identifies muscle edema and inflammation; identifies fatty replacement in advanced IBM.
  6. Muscle Biopsy: ◦ Required to distinguish IMs if no characteristic rash or MSAs are present. ◦ Mandatory for all suspected PM cases to exclude IBM. ◦ Selection: Choose a clinically affected but not too weak muscle (e.g., MRC grade 4/5).

MANAGEMENT & TREATMENT

  1. Glucocorticoids: ◦ Prednisone (Oral): 0.75–1.5 mg/kg per day to start. ◦ Prednisone (IV): 1 g in 100 mL normal saline over 1–2 h, daily or every other day for 3–6 doses.
  2. Immunotherapies: ◦ Azathioprine (Oral): 2–3 mg/kg per day; single a.m. dose. ◦ Azathioprine (Subcutaneous): 7.5–20 mg weekly or 20–50 mg weekly. ◦ Cyclophosphamide (Oral): 1.5–2 mg/kg per day; single a.m. dose. ◦ Cyclophosphamide (IV): 0.5–1.0 g/m² per month × 6–12 months. ◦ Cyclophosphamide (Alternative Oral): 4–6 mg/kg per day, split into two daily doses. ◦ Tacrolimus (Oral): 0.1–0.2 mg/kg per day in two divided doses. ◦ Tacrolimus (IV): Adults (1–1.5 g BID); Children (600 mg/m² per dose BID). Note: No >1 g/d in renal failure. ◦ IVIG: 2 g/kg over 2–5 days; then 1 g/kg every 4–8 weeks as needed. ◦ IVIG (Alternative): 750 mg/m² (up to 1 g) repeated in 2 weeks, then every 6–18 months.

PROGNOSIS & COMPLICATIONS

• Malignancy: High risk in DM (especially with anti-TIF1-γ or anti-NXP2) and IMNM. ◦ Note: Risk of cancer is lower in PM than in DM. ◦ No increased risk of malignancy in IBM. • Pulmonary: ◦ Rapidly progressive ILD associated with anti-MDA5. ◦ Mild ILD associated with anti-SAE. ◦ Lung involvement in ASyS is a defining feature. • Other Complications: Myocarditis, vasculitis, and other CTDs (especially in DM).

SPECIAL POPULATIONS

• Pediatric Patients: Juvenile DM may present with similar features to adult DM. ◦ Note: IBM does not occur in children. ◦ Anti-HMGCR myopathy can occur in children/young adults without statin use. ◦ Anti-SRP myopathy is often aggressive and refractory. ◦ Age >50: High suspicion for IBM; requires biopsy to exclude from PM. ◦ Statin Users:** ◦ Anti-HMGCR myopathy may be triggered by statins (especially in those >50). ◦ Unlike 'toxic' myopathy, anti-HMGCR myopathy does not improve with statin discontinuation.

KEY PEARLS & HIGH-YIELD POINTS

• CK Threshold: CK > 2000 U/L is a highly specific indicator of myopathy. ◦ Table 377-1 Summary: ◦ DM: Perimysial/perivascular inflammation; MxA & MHC-1 expression. ◦ PM: Endomysial infiltration; CD8+ T cells. ◦ IMNM: Necrotic fibers; minimal inflammation; HMGCR/SRP antibodies. ◦ ASyS: Perimysial fragmentation; MAC deposition on sarcolemma. ◦ IBM: Rimmed vacuoles; p62, LC3, TDP-43 aggregates; 15–18 nm tubulofilaments. ◦ Malignancy Screening: Essential in DM (especially anti-TIF1-γ/NXP2) and IMNM. ◦ Symptom Duration: IBM has a long progression (~15 years to wheelchair). ◦ Treatment Monitoring: ◦ Prednisone: Monitor weight, BP, glucose, potassium, cataracts. ◦ Tacrolimus: Monitor BP, creatinine/BUN, liver enzymes, tacrolimus levels. ◦ IVIG: Monitor heart rate, blood pressure, creatinine/BUN.

Reference Tables

TABLE 377-1 Inflammatory Myopathies: Clinical and Laboratory Features DISORDER DM

Harrison's 22e, p.2910

DISORDER SEX AGE OF
ONSET		 RASH PATTERN OF
WEAKNESS		 LABORATORY
FEATURES		 MUSCLE BIOPSY CELLULAR
INFILTRATE		 RESPONSE
TO IS
THERAPY		 COMMON
ASSOCIATED
CONDITIONS
DM F > M Childhood
and adult		 Yes Proximal >
distal		 Normal or increased
CK (up to 50× normal
or higher); various
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		 Yes Myocarditis,
ILD,
malignancy,
vasculitis,
other CTDs
F > M Adult No Proximal >
distal		 Increased CK (up to
50× normal or higher)		 Endomysial and
perivascular inflammation;
ubiquitous expression of
MHC-1		 CD8+ T cells;
macrophages;
plasma cells		 Yes
IMNM M = F Children
and adults		 No Proximal >
distal		 Elevated CK (>10×
normal or higher);
anti-HMGCR or anti-
SRP antibodies		 Necrotic muscle fibers;
minimal inflammatory
infiltrate; MHC-I and MAC
deposition on sarcolemma
of scattered nonnecrotic
muscle fibers		 Macrophages
in necrotic
fibers
undergoing
phagocytosis		 Yes Malignancy,
CTD, HMGCR
antibody
cases can be
triggered by
statin use
F > M Children
and adults		 Sometimes Proximal >
distal		 Elevated CK (>10×
normal or higher);
antisynthetase
antibodies		 Perimysial and
perivascular inflammation;
perimysial fragmentation
with alkaline phosphatase
staining; perimysial muscle
damage with necrosis;
MHC-I, HLA-DR, and MAC
deposition on sarcolemma
of perifascicular muscle
fibers		 CD4+ dendritic
cells; B cells;
macrophages		 Yes
IBM M > F Older adults
(>50 years)		 No Proximal
and distal;
predilection
for: finger/
wrist
flexors, knee
extensors		 Normal or mildly
increased CK (usually
<10× normal); anti-
cN-1A antibodies;
large granular
lymphocytes on
flow cytometry and
reduced CD4/CD8
ratio with increased
CD8 count		 Endomysial and
perivascular inflammation;
ubiquitous expression
of MHC-1 and HLA-DR;
rimmed vacuoles; p62, LC3,
TDP-43 aggregates; EM:
15–18 nm tubulofilaments;
ragged red and COX-
negative fibers		 CD8+ T cells;
macrophages;
plasma cells;
myeloid
dendritic cells;
large granular
lymphocytes		 None or
minimal		 Granular
lymphocytic
leukemia/
lymphocytosis,
sarcoidosis,
sicca or
Sjögren’s
syndrome

TABLE 377-2 Immunotherapies for Inflammatory Myopathies THERAPY Prednisone

Harrison's 22e, p.2916

THERAPY ROUTE DOSE SIDE EFFECTS MONITOR
Prednisone Oral 0.75–1.5 mg/kg per day to start Hypertension, fluid and weight gain,
hyperglycemia, hypokalemia, cataracts,
gastric irritation, osteoporosis, infection,
aseptic femoral necrosis		 Weight, blood pressure, serum
glucose/potassium, cataract
formation
Intravenous 1 g in 100 mL/normal saline over 1–2 h,
daily or every other day for 3–6 doses		 Arrhythmia, flushing, dysgeusia,
anxiety, insomnia, fluid and weight gain,
hyperglycemia, hypokalemia, infection
Azathioprine Oral 2–3 mg/kg per day; single a.m. dose Flu-like illness, hepatotoxicity, pancreatitis,
leukopenia, macrocytosis, neoplasia,
infection, teratogenicity		 Blood count, liver enzymes
Oral
Subcutaneously		 7.5–20 mg weekly, single or divided doses;
1 day a week dosing
20–50 mg weekly; 1 day a week dosing		 Hepatotoxicity, pulmonary fibrosis, infection,
neoplasia, infertility, leukopenia, alopecia,
gastric irritation, stomatitis, teratogenicity
Same as oral
Cyclophosphamide Oral
Intravenous		 1.5–2 mg/kg per day; single a.m. dose
0.5–1.0 g/m2 per month × 6–12 months		 Bone marrow suppression, infertility,
hemorrhagic cystitis, alopecia, infections,
neoplasia, teratogenicity		 Blood count, urinalysis
Oral 4–6 mg/kg per day, split into two daily
doses		 Nephrotoxicity, hypertension, infection,
hepatotoxicity, hirsutism, tremor, gum
hyperplasia, teratogenicity
Tacrolimus Oral 0.1–0.2 mg/kg per day in two divided doses Nephrotoxicity, hypertension, infection,
hepatotoxicity, hirsutism, tremor, gum
hyperplasia, teratogenicity		 Blood pressure, creatinine/
BUN, liver enzymes, tacrolimus
levels
Oral Adults (1–1.5 g BID)
Children (600 mg/m2 per dose BID)
(no >1 g/d in patients with renal failure)		 Bone marrow suppression, hypertension,
tremor, diarrhea, nausea, vomiting, headache,
sinusitis, confusion, amblyopia, cough,
teratogenicity, infection, neoplasia
Intravenous
immunoglobulin		 Intravenous 2 g/kg over 2–5 days; then 1 g/kg every 4–8
weeks as needed		 Hypotension, arrhythmia, diaphoresis,
flushing, nephrotoxicity, headache, aseptic
meningitis, anaphylaxis, stroke		 Heart rate, blood pressure,
creatinine/BUN
Intravenous A course is typically 750 mg/m2 (up to 1 g)
and repeated in 2 weeks
Courses are then repeated usually every
6–18 months		 Infusion reactions (as per IVIG), infection,
progressive multifocal leukoencephalopathy