Dermatomyositis (DM)

Definition and Epidemiology

Definition

Dermatomyositis (DM) is an idiopathic, immune-mediated, inflammatory myopathy that causes progressive, symmetric, proximal muscle weakness and characteristic cutaneous manifestations.

Antisynthetase syndrome is a subtype of DM characterized by the presence of antisynthetase antibodies and accompanied by certain extramuscular manifestations.

Epidemiology

• Incidence: 0.5–8.4 cases per million
• Women are twice more likely to be affected.
• Bimodal age of presentation:
  • 5–15 years of age
  • 45–60 years of age
• Peak onset is at about 50 years of age.

Etiology and Pathophysiology

Etiology

• Exact etiology unknown
• Possible genetic factors:
  • HLA-DR3
  • HLA-DR5
  • HLA-DR7
• Environmental triggers:
  • Infectious:
    • Coxsackie B virus
    • Enterovirus
    • Parvovirus
    • Human T cell lymphotropic virus type-1 (HTLV-1)
    • Toxoplasma
    • Borrelia
  • Medications:
    • NSAIDs (diclofenac)
    • Antibacterials (penicillin, sulfonamides)
    • Antineoplastic agents (hydroxyurea, cyclophosphamide)
    • Interferons
    • Anti-tumor necrosis factor drugs
    • Statins
  • Ultraviolet (UV) light
• Predisposing health conditions:
  • Smoking
  • Vitamin D deficiency
  • Malignancy

Pathophysiology

• In muscles:
  • Complement activation and antibody production → immune-complex deposition onto endomysial capillaries and arterioles
  • Associated with infiltration of B lymphocytes, dendritic cells, macrophages, and CD4 T cells within the perivascular and perimysial space
  • Inflammation → destruction of capillaries → microinfarction of muscle → muscle atrophy and degeneration
    • Perifascicular atrophy is seen initially.
    • Necrotic and degenerative fibers are late findings.
• In the skin:
  • Pathogenesis of DM is poorly understood.
  • Likely similar to muscle involvement
  • Results in:
    • Hyperkeratosis and dyskeratosis (abnormal keratinization of cells within the stratum spinosum)
    • Vacuolar changes in the basal layer
    • ↑ Lymphocytic infiltrate
    • Mucin deposition

Clinical Presentation

Musculoskeletal manifestations

• Muscle weakness 
  • Involves proximal muscles:
    • Deltoids
    • Hip flexors
    • Neck flexors
  • Symmetric
  • Develops over weeks to months
  • Mainly noted when: 
    • Climbing stairs
    • Brushing hair
    • Standing up from a seated position
• Muscles are rarely tender.
• Muscle atrophy may be noted.
• Non-erosive arthralgia or arthritis: seen in antisynthetase syndrome

Cutaneous manifestations

• Heliotrope rash:
  • Pathognomonic feature
  • Erythematous rash around the upper eyelids
  • Periorbital edema
• Gottron’s papules:
  • Pathognomonic feature
  • Symmetric
  • Erythematous papules
  • Located on the dorsal metacarpophalangeal and interphalangeal joints
• Facial erythema:
  • “Butterfly” pattern that mimics the malar rash of lupus
  • Involves the nasolabial folds
• Gottron’s sign: 
  • Erythematous macules or patches
  • Often on extensor surfaces (e.g., hands, elbows, knees, and ankles)
• Photodistributed poikiloderma:
  • Hypo- and hyperpigmentation
  • Mild epidermal atrophy
  • Telangiectasias
  • Involves light-exposed sites (including the scalp):
    • Shawl sign: involves the upper back, posterior neck, and shoulders
    • V-sign: involves the upper chest, anterior neck, and shoulders
    • Holster sign: involves the lateral aspects of the thighs
• Nail changes:
  • Dilated capillary loops at the proximal nailfold
  • Periungal erythema
  • Cuticle hypertrophy
• Calcinosis cutis (common in children): deposition of calcium within the skin
• “Mechanic’s hands”:
  • Hyperkeratotic eruptions over the finger pads and lateral aspects of fingers
  • Associated with antisynthetase syndrome

Systemic manifestations

• General:
  • Fatigue
  • Fever
  • Weight loss
  • Raynaud’s phenomenon
• Respiratory:
  • Interstitial lung disease:
    • Dry cough
    • Dyspnea
    • Bilateral crackles
    • Seen in antisynthetase syndrome
  • Diaphragm and chest-wall muscle weakness:
    • Respiratory insufficiency
• GI:
  • Pharyngeal and esophageal muscle involvement:
    • Dysphagia
    • Dysphonia
    • Gastroesophageal reflux
  • Gastritis and gastric ulcers (more common in children)
• Cardiovascular:
  • Atrioventricular conduction abnormalities
  • Myocarditis
  • Dilated cardiomyopathy

Diagnosis

Diagnostic workup

• Initial laboratory tests:
  • CBC:
    • Leukocytosis
    • Thrombocytosis
  • Inflammatory markers
    • ↑ Erythrocyte sedimentation rate (ESR)
    • ↑ CRP
  • Muscle enzymes (used to monitor response to therapy)
    • ↑ CK
    • ↑ Aldolase
    • ↑ AST and ALT
    • ↑ LDH
  • ANA positivity
    • Non-specific and not diagnostic
• Followed-up with myositis-specific antibody testing:
  • Anti-Jo-1 antibodies 
    • Anti-histidyl tRNA synthetase antibody
    • Seen in antisynthetase syndrome
    • Occurs in 20%‒30% of patients
  • Anti-Mi-2 antibodies 
    • Seen in 10% of patients
    • Highly specific, but low sensitivity
  • Anti-signal recognition protein (anti-SRP) antibodies 
    • Specific for inflammatory myopathies
    • Associated with severe myositis
• Additional studies if the diagnosis is unclear due to non-specific or atypical findings:
  • Electromyography (EMG) 
    • Comprises nerve-conduction studies that include repetitive nerve stimulation and needle examination of muscles
    • Altered in 90% of cases of DM
    • Can support the diagnosis, but is not diagnostic
  • Muscle biopsy and histopathology
    • Most accurate test to confirm the diagnosis
    • Findings: capillary injury, perifascicular atrophy and fibrosis, and inflammatory cell infiltrate

Evaluation of systemic manifestations

• Interstitial lung disease:
  • Chest radiography
  • Pulmonary function tests
• Dysphagia:
  • Barium-swallow study
  • Esophageal manometry
• Conduction abnormalities: ECG
• Myocarditis or cardiomyopathy: echocardiography

Screening for malignancy

• Patients diagnosed with DM should be evaluated for a possible underlying malignancy.
• Workup is directed based on the patient’s age and gender.
• Initial workup:
  • Mammography
  • Pap smear
  • Colonoscopy
  • CT of thorax, abdomen, and pelvis
• Additional studies are ordered based on risk factors, symptoms, or an abnormal initial workup:
  • Cancer antigen 125 (CA 125)
  • Transvaginal ultrasound (for patients at high risk of ovarian cancer)
  • Upper endoscopy (for esophageal cancer)
  • MRI
  • PET

Management

Management of DM is directed toward the restoration of muscle strength and minimization of inflammation.

• Rheumatology consultation
• Medical therapy:
  • Systemic glucocorticoids (1st-line therapy):
    • Usually needed for 9–12 months
    • Slowly tapered off
    • Muscle enzymes are used to monitor response to therapy.
  • Immunosuppressants:
    • Methotrexate, azathioprine
    • Used to reduce steroid requirements and the risk of steroid-induced complications
  • IV immunoglobulin (IVIG):
    • For patients with life-threatening weaknesses (e.g., severe dysphagia, respiratory insufficiency)
    • Provides more rapid onset of action than steroids
  • For recurrent or refractory disease:
    • Rituximab
    • Mycophenolate mofetil
    • Tacrolimus
• Physiotherapy to maintain and improve muscular function
• Management of cutaneous manifestations:
  • Protective clothing and SPF protection using sunblock
  • Avoiding sunlight and UV radiation (tanning beds)
• Management of dysphagia:
  • Speech therapy
  • Elevate the head of the bed
  • Diet modifications
  • Enteral feeding for patients with severe dysphagia
• Prophylaxis (while on long-term corticosteroids):
  • Osteoporosis: 
    • Calcium and vitamin D supplementation
    • Bisphosphonates in high-risk patients or individuals with osteoporosis
  • Pneumocystis jirovecii: trimethoprim-sulfamethoxazole
  • Appropriate immunization

Complications and Prognosis

Complications

• Cardiac involvement (50% of cases): 
  • Conduction abnormalities → arrhythmia
  • Myocarditis or dilated cardiomyopathy → heart failure
  • ↑ Risk of myocardial infarction
• Respiratory complications:
  • Interstitial lung disease (30% of cases) → pulmonary hypertension and cor pulmonale
  • Aspiration pneumonia due to dysphagia
• Malignancy (25% of cases): 
  • Patients with DM have a significantly ↑ risk (5–7 fold)
  • Often within the 1st year after the diagnosis of DM
  • Most common: lung, breast, ovarian, stomach, pancreatic, prostate, bladder, and colorectal cancer, and non-Hodgkin’s lymphoma
• Adverse effects of medical therapy: 
  • Corticosteroid therapy: 
    • Osteoporosis and compression fractures
    • Insulin resistance → diabetes mellitus
    • Hypertension
    • Dyslipidemia
    • Weight gain
    • Growth delay in children
    • Steroid-induced myopathy
  • Immunosuppressive therapy:
    • Opportunistic infections
    • Upper respiratory tract infections and pneumonia
    • Skin infections
    • Bacteremia and sepsis

Prognosis

• Relapse:
  • Occurs in the majority of patients
  • May occur at any time
• Approximately 25% of patients have persistent muscle weakness or disability.
• Mortality: 
  • 5-year survival rate is 75%
  • Higher mortality in patients > 65 years of age
  • Often secondary to:
    • Heart failure
    • Interstitial lung disease
    • Infections (opportunistic or non-opportunistic)
    • Malignancy

Differential Diagnosis

• Polymyositis: an autoimmune, inflammatory myopathy due to T cell-mediated muscle injury. Patients present with symptoms similar to DM, but lack the characteristic cutaneous manifestations. Diagnosis is based on the clinical presentation and antibody evaluation, and may be confirmed with biopsy. Management is with systemic glucocorticoids, immunosuppressive medications, and screening for malignancy.
• Inclusion body myositis: an inflammatory myopathy characterized by slowly progressing muscle weakness. However, the weakness is asymmetrical and involves distal muscles, especially those of the hands. On physical examination, there is significant muscle atrophy and a lack of cutaneous lesions. The diagnosis is confirmed with a biopsy, which shows inclusion bodies within the muscle tissue. Inclusion body myositis is refractory to steroids and must be excluded in refractory cases of DM.
• Hypothyroidism: a thyroid-hormone deficiency that can result from disorders of the thyroid, hypothalamus, or pituitary gland. Proximal muscle weakness is a common presenting complaint. Patients usually have multiple other systemic manifestations, such as cold intolerance, neuropsychiatric changes, dry skin, constipation, and bradycardia. Thyroid function tests can provide the diagnosis, and management involves thyroid hormone replacement.
• Myasthenia gravis: a condition accompanied by episodic muscle weakness and fatigability, resulting from autoantibodies to acetylcholine receptors (AChR). Myasthenia gravis usually involves the bulbar and ocular muscles and is brought on by activity. There are no cutaneous manifestations. Diagnosis is based on the measurement of AChR antibodies, EMG, and edrophonium challenge. Management is with anticholinesterases, immunosuppressants, steroids, and IVIG.
• Cushing’s syndrome: an endocrine disorder characterized by chronic exposure to exogenous or endogenous corticosteroids. Patients with Cushing’s syndrome may display proximal muscle weakness due to atrophy of the gluteal and upper leg muscles. The characteristic truncal obesity, moon facing, and easy bruising may also be present. Diagnosis is based on clinical history and cortisol studies. Management depends on the underlying cause.
• Systemic lupus erythematosus: a multisystem autoimmune disorder that occurs predominantly in young women. The classic malar rash is similar to that in DM, except for sparing of the nasolabial folds. Associated conditions include arthritis, Raynaud’s phenomenon, pleuritis, renal disease, and neuropsychiatric symptoms. Diagnosis requires meeting the clinical and serological criteria. Management is with corticosteroids and immunosuppressants.
• Polymyalgia rheumatica: an inflammatory condition that affects adults > 55 years of age. Patients present with pain and stiffness of the proximal muscles. There is no muscle weakness or atrophy. Diagnosis is clinical, and based on the determination of elevated inflammatory markers. Management is with corticosteroids. Patients should be evaluated for temporal arteritis.