Chapter 377: Inflammatory Myopathies¶
Chapter 377 | Part 11: Immune-Mediated, Inflammatory, and Rheumatologic Disorders
KEY CLINICAL POINTS¶
- Inflammatory myopathies (IMs) include dermatomyositis (DM), polymyositis (PM), immune-mediated necrotizing myopathy (IMNM), antisynthetase syndrome (ASyS), and inclusion body myositis (IBM).
- Key diagnostic features include proximal muscle weakness, characteristic rashes (heliotrope, Gottron papules), elevated creatine kinase (CK), and myositis-specific autoantibodies (MSAs).
- Treatment varies by subtype: glucocorticoids as first-line for DM/PM, IVIG for anti-HMGCR myopathy, and immunosuppressants for IMNM/ASyS. IBM requires physical therapy and swallowing management.
- Prognosis is generally favorable for DM/PM but poor for IBM, with progressive muscle atrophy and disability. Malignancy risk is elevated in DM and IMNM.
- Diagnostic workup includes CK levels, muscle biopsy, MRI, and MSAs. Differential diagnosis includes muscular dystrophy, polymyalgia rheumatica, and paraneoplastic syndromes.
1. DEFINITION & OVERVIEW¶
Inflammatory myopathies (IMs) are a group of autoimmune disorders characterized by chronic muscle inflammation, weakness, and muscle biopsy findings of inflammatory infiltrates. Key subtypes include dermatomyositis (DM), polymyositis (PM), immune-mediated necrotizing myopathy (IMNM), antisynthetase syndrome (ASyS), and inclusion body myositis (IBM). These conditions are distinct from infectious, toxic, and hereditary myopathies.
Table 377-1: Inflammatory Myopathies: Clinical and Laboratory Features¶
| DISORD ER | SEX | AGE OF ONSET | RASH | PATTER N OF W EAKNE SS | LABOR ATORY FEATU RES | MUSCL E BIOPSY | CELLUL AR INFI LTRATE | RESPO NSE TO THERA PY | COMMO N ASSO CIATED CONDIT IONS |
|---|---|---|---|---|---|---|---|---|---|
| DM | F > M | Childhoo d and adult | Yes | Proximal > distal | Normal or increa sed CK (up to 50× normal or higher); various MSAs (a nti-MDA 5, anti-TI F1, anti- Mi-2, ant i-NXP2) | Perimysi al and p erivascul ar inflam mation; IFN-1 re gulated proteins (MHC-1, MxA), MAC de position on capill aries | CD4+ dendritic cells; B cells; ma crophag es | Yes | Myocard itis, ILD, maligna ncy, vas culitis, other CTDs |
| PM | F > M | Adult | No | Proximal > distal | Increase d CK (up to 50× normal or higher) | Endomy sial and perivasc ular infla mmation ; ubiquit ous expr ession of MHC-1 | CD8+ T cells; ma crophag es; plasma cells | Yes | |
| IMNM | M = F | Children and adults | No | Proximal > distal | Elevated CK (>10× normal or higher); anti-HM GCR or anti-SRP antibodi es | Necrotic muscle fibers; minimal i nflamma tory infiltrate; MHC-I and MAC de position on sarco lemma of scatte red nonn ecrotic muscle fibers | Macroph ages in necrotic fibers un dergoing phagocy tosis | Yes | Maligna ncy, CTD, HMGCR antibody cases can be triggered by statin use |
| DISORD ER | SEX | AGE OF ONSET | RASH | PATTER N OF W EAKNE SS | LABOR ATORY FEATU RES | MUSCL E BIOPSY | CELLUL AR INFI LTRATE | RESPO NSE TO THERA PY | COMMO N ASSO CIATED CONDIT IONS |
|---|---|---|---|---|---|---|---|---|---|
| ASyS | F > M | Children and adults | Sometim es | Proximal > distal | Elevated CK (>10× normal or higher); antisynth etase an tibodies | Perimysi al and p erivascul ar inflam mation; perimysi al fragm entation with alkaline phospha tase staining; perimysi al muscle damage with necrosis; MHC-I, HLA-DR, and MAC de position on sarco lemma of perifa scicular muscle fibers | CD4+ dendritic cells; B cells; ma crophag es | Yes | Nonerosi ve arthritis, ILD, Ray naud’s p henome non, fever |
| IBM | M > F | Older adults (>50 years) | No | Proximal and distal; pr edilectio n for: fin ger/wrist flexors, knee ext ensors | Normal or mildly increase d CK (usually <10× normal); anti-cN- 1A antib odies; large granular lymphoc ytes on flow cyto metry and reduced CD4/CD 8 ratio with incr eased CD8 count | Endomy sial and perivasc ular infla mmation ; ubiquit ous expr ession of MHC-1 and HLA-DR; rimmed vacuoles ; p62, LC3, TDP-43 aggregat es; EM: 15–18 nm tubul ofilamen ts; ragged red and COX-ne gative fibers | CD8+ T cells; ma crophag es; plasma cells; myeloid dendritic cells; large granular lymphoc ytes | None or minimal | Granular lymphoc ytic leuk emia/lym phocytos is, sarcoi dosis, sicca or Sjögren’ s syndro me |
1.1 Classification¶
IMs are classified based on clinical features, autoantibodies, and histopathology. Key subtypes include: - Dermatomyositis (DM): Characterized by skin rash and proximal weakness. - Polymyositis (PM): Symmetric proximal muscle weakness without skin rash. - Immune-mediated necrotizing myopathy (IMNM): Necrotic muscle fibers with minimal inflammation. - Antisynthetase syndrome (ASyS): Autoimmune myopathy with ILD, arthritis, and Raynaud’s phenomenon. - Inclusion body myositis (IBM): Progressive muscle atrophy with inclusion bodies on biopsy.
1.2 Diagnostic Criteria¶
Diagnosis requires combination of clinical features (proximal weakness, rash), elevated CK, muscle biopsy, and myositis-specific autoantibodies (MSAs). The 2011 EULAR/ACR criteria for IMs include: - Clinical features (weakness, rash) - Laboratory findings (elevated CK) - Muscle biopsy findings (inflammatory infiltrates, necrosis) - Presence of MSAs (anti-MDA5, anti-Jo-1, etc.)
2. EPIDEMIOLOGY¶
The incidence of inflammatory myopathies grouped together is up to 16 cases per 100,000, with prevalence in the range of 14–32 per 100,000. DM is more common in women, while IBM is more common in men. DM can occur in children (juvenile DM), while IBM always occurs in adults. The risk of malignancy is higher in adult-onset DM (~15% within 2–3 years) and IMNM. Gastrointestinal involvement varies by population (up to 50% in the Far East but rare in the Middle East).
2.1 Risk Factors¶
Genetic predisposition (HLA associations), environmental triggers (infections, statin use), and immune dysregulation. Female sex is a risk factor for DM and ASyS, while male sex is a risk factor for IBM. Older age is a risk factor for IBM and IMNM.
2.2 Demographics¶
DM: More common in women (F > M), occurs in children and adults. PM: More common in women, occurs in adults. IBM: More common in men (>50 years). ASyS: More common in children and adults. IMNM: Can occur in children and adults, often associated with malignancy or statin use.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
IMs are autoimmune disorders with complex pathogenesis involving type I interferon (IFN) pathways, autoantibodies, and immune cell infiltration. Key mechanisms include: - Autoantibodies (anti-MDA5, anti-Jo-1, anti-HMGCR) directly target muscle proteins. - Type I IFN-mediated microvasculopathy and muscle damage. - Inflammatory cell infiltration (CD8+ T cells, macrophages) in muscle tissue. - Protein misfolding and ER stress in IBM and IMNM.
3.1 Autoantibodies¶
Myositis-specific autoantibodies (MSAs) are diagnostic and pathogenic: - Anti-MDA5: Associated with ILD and skin ulcerations. - Anti-Jo-1: Linked to ASyS and ILD. - Anti-HMGCR: Seen in statin-induced IMNM. - Anti-SRP: Associated with IMNM and ILD. - Anti-NXP-2: Linked to calcinosis and dysphagia.
3.2 Molecular Pathways¶
Type I IFN signaling drives microvasculopathy and muscle inflammation. HMGCR antibodies disrupt lipid metabolism, leading to muscle necrosis. TDP-43 mislocalization in IBM causes RNA splicing defects and protein aggregation.
4. CLINICAL FEATURES¶
Key clinical features include proximal muscle weakness, characteristic rashes (heliotrope, Gottron papules), dysphagia, and systemic manifestations (ILD, arthritis). IBM presents with asymmetric weakness and progressive atrophy. IMNM is often asymptomatic until muscle necrosis occurs.
4.1 Dermatomyositis (DM)¶
Symmetric proximal weakness, heliotrope rash, Gottron papules, and V-sign. Associated with ILD, malignancy, and vasculitis. Juvenile DM may present with skin-only disease (amyopathic DM).
4.2 Polymyositis (PM)¶
Symmetric proximal weakness without skin rash. May present with interstitial lung disease (ILD) or malignancy. Heterogeneous pathogenesis with variable response to immunotherapy.
4.3 Immune-Mediated Necrotizing Myopathy (IMNM)¶
Acute or insidious onset of proximal weakness. Often asymptomatic until muscle necrosis occurs. Associated with malignancy, statin use, or autoimmune conditions.
4.4 Antisynthetase Syndrome (ASyS)¶
Myositis with ILD, arthritis, Raynaud’s phenomenon, and mechanic hands. Often presents with fever and interstitial lung disease. Linked to anti-Jo-1 antibodies.
4.5 Inclusion Body Myositis (IBM)¶
Progressive weakness and atrophy of wrist/finger flexors and quadriceps. Characterized by rimmed vacuoles and inclusion bodies on biopsy. Often resistant to immunotherapy.
5. DIFFERENTIAL DIAGNOSIS¶
Differential diagnoses include muscular dystrophy, polymyalgia rheumatica, paraneoplastic syndromes, and infectious myopathies. Key distinguishing features include: - Skin rash (DM vs PM) - CK levels (normal in IBM) - Presence of MSAs (DM, ASyS, IMNM) - Muscle biopsy findings (necrosis vs inflammation) - Response to immunotherapy (IBM is resistant).
5.1 Non-IM Myopathies¶
Muscular dystrophy (progressive weakness, no rash), polymyalgia rheumatica (older adults, normal CK), paraneoplastic syndromes (malignancy association), and toxic myopathies (statin use).
5.2 Overlap Syndromes¶
IMs associated with connective tissue diseases (CTDs) like scleroderma, Sjögren’s, or lupus. These syndromes respond well to immunosuppression.
6. INVESTIGATIONS & DIAGNOSIS¶
Diagnostic workup includes CK levels, muscle MRI, EMG, and muscle biopsy. MSAs are critical for subtype differentiation. Pulmonary function tests and imaging are used for ILD assessment.
6.1 Laboratory Tests¶
Elevated CK (especially in DM, PM, IMNM). Normal CK in IBM. Anti-nuclear antibodies (ANA) are nonspecific. MSAs (anti-MDA5, anti-Jo-1, etc.) are diagnostic.
6.2 Imaging¶
Muscle MRI shows edema/inflammation in DM/PM, selective involvement in IBM. Chest CT for ILD in ASyS/IMNM. EMG shows increased insertional activity and spontaneous potentials.
6.3 Muscle Biopsy¶
Key findings include perifascicular atrophy (DM), endomysial inflammation (PM), necrotic fibers (IMNM), and inclusion bodies (IBM). Immunohistochemistry for MxA, MHC-I, and MSAs.
7. MANAGEMENT & TREATMENT¶
Treatment is tailored to subtype and severity. Glucocorticoids are first-line for DM/PM. IVIG is effective for anti-HMGCR myopathy. Immunosuppressants (azathioprine, methotrexate) are used for IMNM/ASyS. IBM requires physical therapy and swallowing management.
Table 377-2: Immunotherapies for Inflammatory Myopathies¶
| THERAPY | ROUTE | DOSE | SIDE EFFECTS | MONITOR |
|---|---|---|---|---|
| Prednisone | Oral | 0.75–1.5 mg/kg per day to start | Hypertension, hyperglycemia, osteoporosis | Weight, blood pressure, serum glucose/potassium |
| Methylprednisolone | Intravenous | 1 g in 100 mL/normal saline over 1–2 h, daily or every other day for 3–6 doses | Arrhythmia, fluid and weight gain | Heart rate, blood pressure, serum glucose/potassium |
| Azathioprine | Oral | 2–3 mg/kg per day | Leukopenia, hepatotoxicity, teratogenicity | Blood count, liver enzymes |
| Methotrexate | Oral | 7.5–20 mg weekly | Pulmonary fibrosis, infection, teratogenicity | Liver enzymes, blood count |
| Cyclophosphamide | Oral/Intravenous | 1.5–2 mg/kg per day | Bone marrow suppression, hemorrhagic cystitis | Blood count, urinalysis |
| Cyclosporine | Oral | 4–6 mg/kg per day | Nephrotoxicity, hypertension, infection | Blood pressure, creatinine/BUN |
| THERAPY | ROUTE | DOSE | SIDE EFFECTS | MONITOR |
|---|---|---|---|---|
| Tacrolimus | Oral | 0.1–0.2 mg/kg per day | Nephrotoxicity, hypertension, infection | Blood pressure, creatinine/BUN |
| Mycophenolate Mofetil | Oral | 1.0 g twice daily | Bone marrow suppression, renal toxicity | Blood count, renal function |
| Intravenous Immunoglobulin (IVIG) | Intravenous | 2 g/kg over 2–5 days | Hypotension, anaphylaxis | Heart rate, blood pressure, creatinine/BUN |
7.1 Pharmacologic Therapy¶
Glucocorticoids (prednisone, methylprednisolone) for acute flares. IVIG for anti-HMGCR myopathy. Immunosuppressants (azathioprine, methotrexate, cyclophosphamide) for IMNM/ASyS. TNF inhibitors for severe cases.
7.2 Non-Pharmacologic Therapy¶
Physical therapy to maintain mobility, occupational therapy for daily activities, and swallowing therapy for dysphagia. Avoidance of statins in IMNM patients.
7.3 Surgical Interventions¶
Esophageal dilation or cricopharyngeal myotomy for severe dysphagia. No surgical treatment for IBM or IMNM.
8. PROGNOSIS & COMPLICATIONS¶
Prognosis is generally favorable for DM/PM with treatment, but IBM is progressive and leads to disability. Complications include ILD, malignancy, and steroid myopathy. Mortality is higher in IBM and IMNM with severe complications.
8.1 Survival Rates¶
5-year survival rates for DM: 70–93%. IBM has a poor prognosis with progressive atrophy. IMNM mortality is 20–25% for pulmonary artery aneurysms.
8.2 Complications¶
ILD (common in DM, ASyS, IMNM), malignancy (DM, IMNM), steroid myopathy, and swallowing difficulties (IBM).
9. SPECIAL CONSIDERATIONS¶
Pregnancy: Avoid immunosuppressants (e.g., cyclophosphamide) in the first trimester. Pediatrics: Juvenile DM may present with skin-only disease. Elderly: IBM is more common and resistant to treatment. Statin use: Anti-HMGCR myopathy can mimic muscular dystrophy.
9.1 Pregnancy¶
Avoid cyclophosphamide and methotrexate in the first trimester. Use low-dose prednisone and IVIG as needed.
9.2 Pediatrics¶
Juvenile DM may present with amyopathic DM (skin-only). ASyS is more common in children with ILD.
10. KEY POINTS & CLINICAL PEARLS¶
- Use MSAs and muscle biopsy to differentiate IM subtypes.
- IVIG is effective for anti-HMGCR myopathy and DM.
- IBM is resistant to immunotherapy; focus on physical therapy.
- Monitor for malignancy in DM and IMNM.
- Avoid statins in patients with IMNM or anti-HMGCR antibodies.
- Use low-dose prednisone and taper gradually to minimize steroid side effects.
- Consider overlap syndromes in patients with CTDs and myopathy.
- Muscle MRI is useful for assessing inflammation and guiding biopsy sites.