RheumatologyTier 2Disease (DEADMAN)

Myopathies - dermatomyositis

Description

Idiopathic inflammatory myopathy with characteristic cutaneous disease + symmetrical proximal weakness
Perifascicular muscle injury from complement-mediated microangiopathy - the vessel is the target, not the myofibre

Subtypes

Classic dermatomyositis - rash + myositis
Clinically amyopathic DM (CADM), 10-30% - classic rash, no clinically detectable weakness
- Still carries the malignancy risk and the ILD risk
- Strongly associated with anti-MDA5
Juvenile dermatomyositis - heliotrope rash + Gottron papules + symmetric proximal weakness
- Calcinosis cutis and vasculopathy are far commoner than in adults; malignancy risk is NOT increased
Cancer-associated DM - within 3 years either side of the cancer diagnosis
Overlap DM - with scleroderma, SLE, Sjogren

Cutaneous signs

Heliotrope rash - violaceous discoloration of the upper eyelids with periorbital oedema
Gottron papules - violaceous papules over the extensor surfaces of MCP, PIP, DIP, elbows, knees
- (Gottron sign = the same distribution as macular erythema)
- *Extensor and over the knuckles - contrast SLE, which spares the knuckles and hits the interphalangeal skin*
Shawl sign - photodistributed poikiloderma over the upper back and shoulders
V sign - anterior neck and upper chest
Holster sign - lateral thighs (non-photoexposed, so it argues against simple photosensitivity)
Mechanic's hands - hyperkeratotic, fissured lateral fingers (antisynthetase syndrome)
Nailfold changes - dilated and dropout capillary loops, periungual erythema, ragged cuticles
Calcinosis cutis - juvenile > adult; painful, ulcerating
Severe pruritus (often the most distressing symptom, and distinguishes DM from lupus)

Epidemiology

Incidence ~1/100,000/yr; DM is less common than polymyositis in older series but more reliably diagnosed
Bimodal: juvenile peak 5-15 yr, adult peak 45-65 yr
F:M ~2:1
Malignancy association is adult-only

Aetiopathogenesis

Humoral and interferon-driven, targeting the endothelium
- Complement activation -> membrane attack complex (C5b-9) on endomysial capillaries
- -> capillary dropout -> perifascicular ischaemia and atrophy
- Type I interferon signature is the strongest transcriptional feature
Contrast polymyositis and IBM, where CD8 T cells directly invade non-necrotic myofibres expressing MHC class I

Triggers

Malignancy (paraneoplastic - tumour antigen cross-reactivity, especially anti-TIF1-gamma)
UV exposure; drugs (hydroxyurea, statins, TNF inhibitors, penicillamine, immune checkpoint inhibitors)
Viral infection

Diagnosis

Myositis-specific antibodies - the single most useful stratifier

Antibody	Phenotype
Anti-TIF1-gamma (p155/140)	Highest malignancy risk in adults - severe rash, mild myositis. In children: no malignancy, but severe skin disease
Anti-NXP2	Malignancy risk in adults; calcinosis in juvenile DM
Anti-Mi-2	Classic DM with florid rash, good steroid response, LOW malignancy risk, good prognosis
Anti-MDA5	Amyopathic DM + RAPIDLY PROGRESSIVE ILD; cutaneous ulceration, palmar papules, arthritis. High mortality; commonest in East Asian populations
Anti-SAE	Amyopathic onset then myositis, dysphagia
Anti-Jo-1 and other anti-synthetases (PL-7, PL-12, EJ, OJ)	Antisynthetase syndrome: ILD + myositis + arthritis + mechanic's hands + Raynaud + fever. Anti-Jo-1 is the commonest MSA overall (~20-30% of myositis), but is a minority in DM specifically
Anti-SRP, anti-HMGCR	Immune-mediated necrotising myopathy, very high CK; HMGCR linked to statin exposure

Myositis-associated antibodies (overlap): anti-PM-Scl, anti-Ku, anti-U1RNP, anti-Ro52 (anti-Ro52 with an anti-synthetase predicts severe ILD)
ANA positive in ~80%; a myositis-specific antibody is found in 30-40% (higher with extended panels)

Muscle enzymes

CK raised - but can be normal in CADM and in anti-MDA5 disease
Also AST, ALT, LDH, aldolase raised
- A "hepatitis" with normal GGT in a weak patient is muscle, not liver

EMG

Myopathic: small-amplitude, short-duration, polyphasic motor unit potentials
Plus irritability: fibrillations, positive sharp waves, complex repetitive discharges
Guides which muscle to biopsy - do not biopsy the muscle you needled

MRI

STIR oedema = active inflammation; T1 fatty replacement and atrophy = chronicity; calcification
Best test to target the biopsy site

Muscle biopsy - gold standard

Perifascicular atrophy (near-pathognomonic for DM)
Perivascular and perimysial inflammation - CD4 T cells, B cells, plasmacytoid dendritic cells
MAC (C5b-9) deposition on capillaries, capillary dropout
MHC class I upregulation, MxA staining (interferon)
Skin biopsy: interface dermatitis with mucin - indistinguishable from lupus histologically

2017 EULAR/ACR classification criteria

Weighted score using age at onset, weakness pattern, rash, dysphagia, anti-Jo-1, raised CK, and biopsy features
Probability >=55% = probable; >=90% = definite IIM; subclassification into DM/PM/IBM/JDM follows

Mandatory workup at diagnosis

Malignancy screen - see Associations
HRCT chest and pulmonary function tests including DLCO in everyone (ILD may be asymptomatic)
Swallow assessment - dysphagia predicts aspiration
ECG and echocardiogram - myocarditis, conduction disease
Nailfold capillaroscopy

Management

Axis: severity and organ involvement. Skin, muscle and lung need different drugs, and the malignancy search runs in parallel from day one.

A. Induction

Prednisolone 0.5-1 mg/kg/day (pulse methylprednisolone if severe, dysphagia, or respiratory involvement)
Add a steroid-sparing agent at the same time, not later - steroid monotherapy guarantees toxicity
- Methotrexate or azathioprine first line
- Mycophenolate - preferred if ILD
- Ciclosporin or tacrolimus - especially for ILD and anti-synthetase disease

B. Refractory or severe disease

IVIG - effective for muscle and skin disease
- ProDERM: significantly better response than placebo in active DM; now a licensed indication
- Also the treatment of choice with severe dysphagia or where infection/malignancy limits immunosuppression
Rituximab - refractory DM/PM, particularly anti-synthetase and anti-SRP disease
Cyclophosphamide - severe ILD or vasculitis
JAK inhibitors (tofacitinib, baricitinib) - refractory DM and anti-MDA5 rapidly progressive ILD, targeting the interferon signature
Anti-MDA5 RP-ILD is a medical emergency: early combined glucocorticoid + calcineurin inhibitor + cyclophosphamide, +/- JAK inhibitor, +/- plasma exchange

C. Skin disease - often refractory when muscle disease has settled

Rigorous photoprotection - SPF50+, clothing (UV drives the rash)
Topical corticosteroid or calcineurin inhibitor
Hydroxychloroquine (~1/3 develop a drug eruption - higher than in lupus)
Methotrexate, mycophenolate, IVIG
Antipruritics - the itch is often the dominant symptom

D. Supportive

Physiotherapy and graded exercise from the outset - safe and beneficial, including in active disease
Speech pathology and swallow management; nasogastric feeding if severe
Aspiration precautions
Bone protection (calcium, vitamin D, bisphosphonate), PJP prophylaxis if prednisolone >=20 mg for >4 weeks with a second agent
Vaccination before immunosuppression
Calcinosis: no reliable therapy - diltiazem, bisphosphonate, sodium thiosulfate, surgical excision

E. Malignancy screen

Adults: screen at diagnosis, and repeat annually for 3 years
CT chest/abdomen/pelvis, mammography, transvaginal US + CA-125 (ovarian), colonoscopy, PSA, skin examination
Nasopharyngoscopy in patients of South-East Asian ancestry
PET-CT where available - highest yield single test
Screen most intensively with anti-TIF1-gamma or anti-NXP2; least with anti-Mi-2, anti-MDA5, and anti-synthetase antibodies

F. Monitoring

Manual muscle testing (MMT-8), functional measures, CK trend
CK often falls before strength improves, and can be normal in active skin or lung disease - do not treat the number

Associations

Malignancy - the defining adult association

Risk highest in the first 3-5 years after diagnosis (before and after)
Ovarian, breast, colorectal, lung, gastric, melanoma, non-Hodgkin lymphoma
Nasopharyngeal carcinoma in South-East Asian populations
Anti-TIF1-gamma and anti-NXP2 confer the highest risk; anti-Mi-2, anti-MDA5 and anti-synthetase antibodies confer little or none
Not increased in juvenile dermatomyositis

Pulmonary

ILD in 20-50% - NSIP most common, also OP and UIP
- Anti-MDA5 -> rapidly progressive ILD with high mortality
- Anti-synthetase (Jo-1 and others) -> chronic ILD
Respiratory muscle weakness -> hypoventilation
Aspiration pneumonia from pharyngeal weakness
Pulmonary hypertension

Other

Dysphagia - pharyngeal and upper oesophageal striated muscle
Cardiac: myocarditis, conduction disease, arrhythmia, heart failure (often subclinical)
Raynaud phenomenon
Arthritis/arthralgia
Calcinosis cutis - juvenile disease, anti-NXP2
Overlap CTD: scleroderma, SLE, Sjogren, MCTD
Subcutaneous and mediastinal emphysema (rare, anti-MDA5)

Natural history & complications

Most respond to glucocorticoid plus a steroid-sparing agent, but relapse is common on tapering
Courses: monophasic, polycyclic, or chronic continuous
Skin disease frequently persists after muscle disease remits and drives long-term quality of life
5-yr survival ~75-90%; worse with ILD, malignancy, dysphagia, cardiac involvement, older age

Poor prognostic factors

Underlying malignancy - the dominant determinant
Anti-MDA5 with rapidly progressive ILD - the highest short-term mortality
Dysphagia (aspiration), respiratory or cardiac muscle involvement
Older age at onset, delayed treatment, severe weakness at presentation
Anti-SRP (necrotising myopathy, poor treatment response)

Complications

Respiratory failure - muscle weakness, ILD, aspiration
Dysphagia, malnutrition, aspiration pneumonia
Permanent proximal weakness and functional impairment
Calcinosis with ulceration and infection
Osteoporosis and fracture; steroid myopathy, diabetes, cataract, infection
Malignancy

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