Overlap myositis is an inflammatory myopathy that occurs in conjunction with features of another systemic autoimmune connective tissue disease, such as systemic lupus erythematosus, systemic sclerosis, or rheumatoid arthritis.

Overlap Myositis

Overlap myositis is a subtype of idiopathic inflammatory myopathy (IIM) in which features of an inflammatory myopathy (polymyositis [PM] or dermatomyositis [DM]) coexist with clinical and serological features of one or more other well-defined systemic autoimmune / connective tissue disease (CTD). The word "overlap" literally means two discrete, well-recognised autoimmune diseases existing simultaneously in the same patient — unlike mixed connective tissue disease (MCTD), where each component is present only in an incomplete or mild form.

Overlap = 2 discrete well-defined rheumatic diseases (e.g. lupus + RA = "Rheupus syndrome") — distinguished from MCTD → 2 not-so-discrete, each disease in a mild form ^[1]

Breaking the term down:

"Overlap" → two or more autoimmune conditions overlap in the same patient, each satisfying (or nearly satisfying) its own classification criteria.
"Myositis" → Greek myo- (muscle) + -itis (inflammation) — inflammation of skeletal muscle.

So "overlap myositis" = inflammatory muscle disease occurring in the setting of (overlapping with) another defined CTD such as systemic sclerosis (SSc), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren syndrome (SS), or mixed connective tissue disease (MCTD) ^[2]^[3].

Key Conceptual Distinction — Overlap vs MCTD

Feature	Overlap syndrome	MCTD
Component diseases	Each is well-defined / fully expressed	Each is incomplete / mild
Antibody profile	Antibodies specific to each constituent disease	Anti-U1 RNP is the hallmark
Classic example	Rheupus (erosive RA + lupus nephritis with anti-CCP + anti-dsDNA)	SLE-like + SSc-like + PM-like features with high-titre anti-U1 RNP

2. Epidemiology

Category	Details
Genetic	HLA-DRB1 alleles (particularly HLA-DRB103:01 linked to anti-Jo-1; HLA-DRB111 linked to anti-Mi-2). HLA associations mirror both the myositis component and the overlapping CTD.
Environmental triggers	UV light exposure (DM flares), viral infections (Coxsackie B, parvovirus B19, retroviruses), drugs (statins can trigger necrotising myopathy; D-penicillamine can trigger inflammatory myositis and lupus-like syndrome)
Pre-existing autoimmune disease	Having one CTD increases the risk of developing a second — the "autoimmune tautology" concept
Smoking	Associated with anti-CCP-positive RA and ILD — may predispose to overlap with myositis-associated ILD

3. Anatomy and Function — What Is Being Damaged?

Muscle (epimysium) → Fascicle (perimysium) → Muscle fibre (endomysium) → Myofibril → Sarcomere

Structure	Relevance in Myositis
Endomysium	In polymyositis, CD8+ T-cells invade the endomysium and directly attack individual muscle fibres via MHC-I-mediated cytotoxicity
Perimysium & perimysial blood vessels	In dermatomyositis, B-cell / complement-mediated microangiopathy targets the perimysial capillaries → perifascicular atrophy
Sarcolemma & sarcoplasm	Damaged fibres release creatine kinase (CK), LDH, AST, ALT into the blood — these are the "muscle enzymes" we measure
Proximal muscles (deltoids, hip flexors, neck flexors)	These are large, metabolically active muscles with high blood supply — preferentially affected in inflammatory myopathies

4. Aetiology and Pathophysiology

4.2 Pathophysiology — Muscle Damage

The pathomechanisms differ depending on which IIM subtype constitutes the myositis component of the overlap:

5. Classification

Understanding where overlap myositis sits within the IIM family is essential:

IIM Subtype	Key Features
Dermatomyositis (DM)	Proximal weakness + characteristic skin findings (heliotrope rash, Gottron's papules)
Polymyositis (PM)	Proximal weakness without skin findings (diagnosis of exclusion among IIMs)
Inclusion body myositis (IBM)	Insidious distal + proximal weakness (esp. finger flexors, knee extensors), older males, poor response to immunosuppression
Autoimmune necrotising myopathy (AINM)	Severe proximal weakness, minimal inflammation on biopsy, anti-SRP or anti-HMGCR
Overlap myositis	When associated with collagen vascular disease ^[3]
Antisynthetase syndrome	Anti-synthetase Ab + ILD + myositis + arthritis + mechanic's hands + Raynaud's + fever (some classify this under overlap)
Amyopathic DM	Classic DM skin without clinically evident muscle weakness

Overlap Partner	Common Autoantibody	Clinical Clues
Systemic sclerosis (SSc)	Anti-PM-Scl (anti-PM-Scl75, anti-PM-Scl100)	Sclerodactyly, Raynaud's, ILD, mechanic's hands — this is the most common overlap
SLE	Anti-dsDNA, anti-Sm, anti-U1 RNP	Malar rash, nephritis, serositis, cytopenias
RA	Anti-CCP, RF	Erosive polyarthritis
Sjögren syndrome (SS)	Anti-Ro (SSA), anti-La (SSB)	Sicca symptoms (dry eyes, dry mouth)
MCTD	Anti-U1 RNP (high titre)	Raynaud's, puffy hands, sclerodactyly, myositis, ILD
ANCA-associated vasculitis	MPO-ANCA, PR3-ANCA	Rapidly progressive GN, pulmonary haemorrhage

Features of overlap syndrome: most commonly SSc, SLE, MCTD, less commonly RA, SS ^[2]

This is increasingly the most clinically useful classification because the antibody defines the phenotype:

Antibody	Cutaneous Features	Extracutaneous Features	Overlap Tendency
Anti-Jo-1 (antisynthetase)	Mechanic's hands, Raynaud's	Acute onset, fever, weight loss, myositis, non-erosive arthritis, ILD	High (antisynthetase syndrome)
Anti-SRP	Seldom skin manifestations	Severe myopathy, fibre necrosis, refractory to steroids	Low
Anti-Mi-2	Classic shawl/V sign	Acute DM, responds well to therapy	Low
Anti-MDA5	Cutaneous ulceration (Gottron's, elbows, digital pulps), painful palmar papules, oral ulcers, alopecia	Amyopathic DM, rapidly progressive ILD	Moderate (can overlap with SLE features)
Anti-TIF1γ (p155/140)	Classic DM rash	High association with malignancy	Low
Anti-NXP2 (MJ)	Calcinosis, oedematous DM	Also high association with malignancy	Low
Anti-PM-Scl	Mechanic's hands	ILD, myositis	Very high (SSc-myositis overlap)
Anti-Ku	Non-specific	Myositis + arthritis	Very high (SLE, SSc, overlap)
Anti-U1 RNP	Swollen hands, Raynaud's	Myositis + features of MCTD	Very high

TIF-1 gamma dermatomyositis → high association with malignancy. NXP2 also high association with malignancy ^[4]

High Yield — Myositis-Associated vs Myositis-Specific Antibodies

Myositis-specific antibodies (MSAs): Found only in IIM — diagnostic and prognostic value (e.g. anti-Jo-1, anti-SRP, anti-Mi-2, anti-MDA5, anti-TIF1γ, anti-NXP2)
Myositis-associated antibodies (MAAs): Found in IIM and other CTDs — indicate overlap tendency (e.g. anti-Ro, anti-La, anti-Sm, anti-U1 RNP, anti-PM-Scl, anti-Ku)
"Myositis-associated, e.g. anti-Ro, anti-La, anti-Sm, anti-RNP — also found in association with other rheumatic antibodies" ^[3]

6. Clinical Features

6.1 Symptoms

Symptom	Pathophysiological Basis	Details
Proximal and symmetrical muscle weakness	Inflammatory destruction of large proximal muscles (deltoids, hip flexors) → loss of motor units → weakness	Typically affects the deltoids (shoulder) and the hip flexors (pelvic girdle) ^[5]. Onset is insidious/subacute over weeks to months
Difficulty climbing stairs, rising from chair, squatting	Hip flexor and quadriceps weakness → inability to generate force against gravity at the hip and knee	Early: inability to squat, climb stairs, getting up from chair, carrying heavy groceries ^[2]
Difficulty lifting arms above head (e.g. combing hair, reaching overhead shelves)	Deltoid and shoulder girdle weakness	Reflects shoulder girdle involvement
Difficulty holding head up / head drop	Neck flexor weakness (sternocleidomastoid, scalenes) → inability to maintain head against gravity	Important to test — neck flexors are commonly involved
Dysphagia	Oesophageal striated muscle (upper 1/3) + pharyngeal muscles affected by inflammation → difficulty swallowing	Dysphagia ^[6]; implies pharyngeal/oesophageal involvement; a/w poor prognosis when bulbar muscles involved ^[2]
Dysphonia (voice changes)	Laryngeal and pharyngeal muscle weakness → breathy, quiet, or nasal voice	Late feature
Myalgia and muscle tenderness	Inflammatory infiltrate releasing cytokines (IL-1, TNF-α) → stimulation of muscle nociceptors	Present in 25–50% of cases ^[5]
Fatigue / malaise	Systemic inflammation (elevated IL-6, TNF-α) → constitutional symptoms	Non-specific but prominent

Symptom	Pathophysiological Basis
Violaceous periorbital rash (heliotrope rash)	Complement-mediated microangiopathy in dermal capillaries of the eyelid → vascular congestion and oedema → violaceous discoloration
Itchy or burning rash on sun-exposed areas	Photosensitivity — UV light upregulates MHC-I expression and triggers complement activation in the skin
Cracking/fissuring of the fingertips	Mechanic's hands — hyperkeratosis from chronic low-grade dermal inflammation, especially with antisynthetase syndrome

These depend entirely on which CTD is overlapping. Common patterns include:

Overlapping CTD	Symptoms
SSc	Raynaud's phenomenon (fingers turning white → blue → red), skin tightness, GORD, dyspnoea (ILD)
SLE	Malar rash, photosensitivity, oral ulcers, joint pain, hair loss, pleuritic chest pain, oedema (nephritis)
RA	Symmetrical small-joint polyarthritis (MCPJs, PIPJs, wrists), morning stiffness > 1 hour
Sjögren syndrome	Dry eyes (keratoconjunctivitis sicca), dry mouth (xerostomia), dental caries
MCTD	Raynaud's, puffy/sausage fingers, arthralgia, dyspnoea

Symptom	Pathophysiological Basis
Dyspnoea on exertion	ILD (interstitial lung disease) → fibrosis and thickening of alveolar walls → impaired gas exchange; OR respiratory muscle weakness → hypoventilation
Dry cough	ILD → irritation of airway receptors by fibrotic lung parenchyma
Rapidly progressive breathlessness	Anti-MDA5 associated rapidly progressive ILD — fulminant alveolar damage with extremely high mortality (>50% at 6 months in some series)

ILD (≥10%): associated with anti-Jo1 Ab (antisynthetase). May be associated with rapidly progressive respiratory failure in selected cases ^[2]

6.2 Signs

Sign	How to Elicit	Pathophysiological Basis
Proximal muscle weakness (MRC grading)	Test shoulder abduction (deltoid), hip flexion (iliopsoas), neck flexion against resistance	Loss of functioning motor units due to inflammatory/necrotic myofibre destruction
Preserved/normal deep tendon reflexes	Tap tendons in standard fashion	Reflexes are intact because the peripheral nerve and reflex arc are unaffected (the problem is in the muscle itself, not the nerve) — this distinguishes myopathy from neuropathy
Muscle tenderness	Palpate proximal muscle groups	Ongoing inflammation stimulates muscle nociceptors
Muscle wasting	Inspect and compare bulk	Generally not seen but occurs in severe longstanding disease ^[5]
Waddling gait (Trendelenburg gait)	Observe walking	Pelvic girdle weakness → pelvis drops on the non-weight-bearing side during swing phase → compensatory trunk sway
Gower's sign (especially in children)	Ask patient to rise from the floor	Child "walks hands up their thighs" to compensate for proximal lower limb weakness

Sign	Description	Pathophysiological Basis
Heliotrope rash	Violaceous discoloration of upper eyelid with periorbital oedema ^[2]^[6]	Complement-mediated capillaritis in upper eyelid dermis; "heliotrope" = the colour of the heliotrope flower (purple)
Gottron's papules	Scaly violaceous erythematous plaques over extensor surfaces of MCP/IP joints ^[2]^[6]	Dermal inflammation at sites of mechanical stress (knuckles); pathognomonic for DM
Shawl sign	Photodistributed poikiloderma over the upper back ^[2]	UV-triggered complement activation in dermal vessels of photo-exposed area resembling a shawl draped over the shoulders
V sign	Poikiloderma over the anterior neck and upper chest in a V distribution ^[2]	Same mechanism — photo-exposed V-neck area
Holster sign	Poikiloderma over the lateral aspect of the thighs ^[2]	Not a classically sun-exposed area but still characteristic of DM
Mechanic's hands	Hyperkeratotic, fissured and hyperpigmented skin on palmar and lateral aspects of fingers ^[2]^[5]	Chronic dermal inflammation → epidermal hyperkeratosis; strongly associated with antisynthetase syndrome
Facial erythema (midfacial)	Can mimic lupus malar rash, but often involves nasolabial fold ^[2]	DM facial erythema classically involves nasolabial folds (unlike SLE malar rash which spares them)
Periungual telangiectasia	Dilated nailfold capillaries visible to the naked eye or on capillaroscopy	Microangiopathy of nailfold capillaries — capillary dropout with compensatory dilation of remaining loops
Calcinosis cutis	Hard subcutaneous nodules, especially in juvenile DM	Dystrophic calcification in damaged tissue; calcium and phosphate precipitate in areas of chronic muscle/skin inflammation
Digital vasculitis	Purple-red raised patches on the fingers ^[2]	Complement-mediated endothelial damage in digital arterioles

DM Rash vs SLE Malar Rash — A Classic Exam Trap

DM facial erythema: Involves the nasolabial folds
SLE malar rash: Spares the nasolabial folds ("butterfly" distribution over the cheeks and bridge of nose)
Both are photosensitive, but this anatomical distinction is high-yield for clinical exams

Overlapping CTD	Signs
SSc	Sclerodactyly, digital pitting scars, telangiectasiae, microstomia, salt-and-pepper skin changes, crackles (ILD), elevated JVP (PAH)
SLE	Malar rash (sparing nasolabial folds), discoid lesions, oral ulcers, non-erosive arthritis, pericardial rub, peripheral oedema (nephritis)
RA	Symmetrical polyarthritis with synovial thickening of MCPJs/PIPJs/wrists, swan-neck/boutonnière deformities (late), rheumatoid nodules
Sjögren	Dry eyes (Schirmer test < 5mm/5min), dry mouth, parotid swelling
MCTD	Raynaud's, puffy fingers/hands, synovitis, scleroderma-like skin changes

Sign	Basis
Bilateral fine basal crepitations (Velcro crackles)	ILD → thickened, fibrotic alveolar septa → opening of stiff alveoli produces crackling sounds
Reduced chest expansion	Respiratory muscle weakness or restrictive lung disease from ILD
Tachypnoea	Compensatory response to impaired gas exchange

Feature	Overlap Myositis	Pure PM	Pure DM	IBM	AINM
Weakness pattern	Proximal, symmetric	Proximal, symmetric	Proximal, symmetric	Distal (finger flexors) + proximal (quads)	Proximal, symmetric, severe
Skin findings	Variable (depends on DM component and CTD)	None	Classic DM rash	None	None
Other organ involvement	Multi-organ (defining feature)	Mild	Moderate	Minimal	Minimal
Key antibodies	MAAs (anti-PM-Scl, anti-Ku, anti-U1 RNP) ± MSAs	Anti-Jo-1, anti-SRP	Anti-Mi-2, anti-MDA5, anti-TIF1γ	Anti-cN1A	Anti-SRP, anti-HMGCR
Response to treatment	Generally good (better than pure PM)	Moderate	Good (except anti-MDA5 ILD)	Poor	Variable

Adult form associated with malignancy: 5× risk in dermatomyositis, 2× risk in polymyositis ^[3] Malignancy can occur before, with, or after onset of dermatomyositis ^[2]

Overlap myositis with DM features retains the malignancy risk
In this locality (Hong Kong): NPC is particularly important ^[2]^[3]
Anti-TIF1γ and anti-NXP2 → highest malignancy risk ^[4]
Malignancy screening is mandatory, especially in patients > 40 years, with DM features, and without a known CTD antibody

High Yield Summary

Overlap myositis = inflammatory myopathy (PM or DM) coexisting with another well-defined CTD (most commonly SSc, SLE, MCTD, less commonly RA, Sjögren)
Distinguished from MCTD: overlap has two fully expressed diseases; MCTD has mild/incomplete forms with anti-U1 RNP
Pathophysiology: PM-type (CD8+ T-cell endomysial infiltration) or DM-type (B-cell/complement perimysial microangiopathy), PLUS the pathology of the overlapping CTD
Key antibodies indicating overlap tendency: anti-PM-Scl (SSc overlap), anti-Ku, anti-U1 RNP (MCTD)
Antisynthetase syndrome (anti-Jo-1): myositis + ILD + mechanic's hands + arthritis + Raynaud's + fever — often classified under overlap
Clinical features: proximal symmetric weakness + skin signs (if DM) + features of overlapping CTD + ILD + constitutional symptoms
Malignancy screening is essential, especially in HK: screen for NPC, adenocarcinomas; anti-TIF1γ and anti-NXP2 carry highest risk
Gottron's papules are pathognomonic for DM; DM facial erythema involves nasolabial folds (unlike SLE which spares them)
Prognosis of overlap myositis is generally better than pure PM, but ILD (especially anti-MDA5 associated) is the major driver of mortality

Active Recall - Overlap Myositis

Differential Diagnosis of Overlap Myositis

Detailed Differential Diagnosis Table

These are the closest differentials because they share the core feature of inflammatory proximal weakness. The question is whether the patient has pure PM, pure DM, IBM, AINM, or overlap myositis.

Condition	How to Distinguish from Overlap Myositis	Key Clues
Polymyositis (PM)	No skin findings, no features of another CTD. PM is a "diagnosis of exclusion" among IIMs — you diagnose PM only after ruling out DM, IBM, AINM, and overlap	CK markedly elevated, endomysial CD8+ T-cell infiltrate on biopsy, no CTD-specific autoantibodies
Dermatomyositis (DM)	Has characteristic skin findings (heliotrope rash, Gottron's papules) but does NOT have features meeting criteria for another CTD	Proximal muscle weakness and cutaneous manifestations over weeks to months; dysphagia; myalgia; violaceous periorbital oedematous rash (heliotrope rash); erythematous lesions on extensor surfaces of joints (Gottron's papules); associated with malignancies ^[8]
Inclusion body myositis (IBM)	More insidious onset and more prominent distal muscle weakness ^[9]. Affects older males (> 50y). Combination of weakness of wrist and finger flexors in UL and weakness of quadriceps and anterior tibial muscles in LL is characteristic ^[9]. Poor response to immunosuppression — this is a critical distinguishing feature	Slowly progressive, asymmetric, distal > proximal pattern; anti-cN1A antibody; rimmed vacuoles + inclusion bodies on muscle biopsy
Autoimmune necrotising myopathy (AINM / IMNM)	Minimal inflammatory infiltrate on biopsy — predominantly necrosis of myofibres. May be triggered by statins (anti-HMGCR) or associated with anti-SRP	Anti-SRP: severe myopathy with muscle fibre necrosis / endomysial fibrosis with minimal inflammatory infiltrates; aggressive disease refractory to high-dose steroids ^[2]
Antisynthetase syndrome	Some classify this under overlap myositis, some as a separate entity. Distinguished by the specific constellation: acute myopathy, fever, ILD, polyarthritis, Raynaud's, mechanic's hand; anti-Jo1 (anti-tRNA-synthetase) ^[10]	Anti-Jo1 or other antisynthetase antibodies; ILD is prominent; mechanic's hands are a strong clue
Clinically amyopathic DM (CADM)	Cutaneous manifestations, but no muscle weakness for ≥ 6 months ^[11]	Anti-MDA5; high risk of rapidly progressive ILD

GC 056 slide — Overlap Myositis: Troyanov classification: Myositis with overlap features (other than rash) and/or "overlap autoAb." With other CTDs: Anti-U1RNP (SLE/MCTD-OM), Anti-PM/Scl, anti-Ku, anti-U3RNP (SSc-OM). Heterogeneous or non-specific muscle histology. Anti-synthetase syndrome: Acute myopathy, fever, ILD, polyarthritis, Raynaud's, mechanic's hand. Anti-Jo1 (anti-tRNA-synthetase). Anti-PL-7, anti-PL-12 (amyopathic variant), anti-OJ, anti-KS, anti-EJ, anti-Zo, anti-Ha-YRS ^[10]

These are critical because overlap myositis by definition involves another CTD — but sometimes the other CTD alone can cause weakness, mimicking the "myositis" component:

Condition	Why It Mimics Overlap Myositis	How to Distinguish
SLE	SLE itself can cause myalgia, mild proximal weakness, and elevated CK. SLE patients may also have Raynaud's, rash, arthritis — all features that could suggest "overlap"	SLE arthritis is typically non-deforming, non-erosive ^[12]. Weakness in SLE is usually mild and disproportionate to the degree of CK elevation; if CK is massively elevated (> 10× ULN), think of true overlap myositis rather than lupus myalgia alone
Systemic sclerosis (SSc)	SSc causes myopathy through fibrosis/atrophy of muscle AND can cause true inflammatory myositis (SSc-myositis overlap, anti-PM/Scl). Coexistence of Raynaud phenomenon and GERD are typically observed in SSc ^[9]	SSc myopathy tends to be milder, with CK only mildly elevated. True SSc-overlap myositis has markedly elevated CK + anti-PM/Scl
Sjögren syndrome (SS)	Can cause inflammatory myositis as an overlap phenomenon. Also causes fatigue that may be mistaken for weakness	Objective signs of keratoconjunctivitis sicca and xerostomia; anti-Ro/SSA and anti-La/SSB ^[9]
Mixed connective tissue disease (MCTD)	MCTD includes myositis as one of its defining features (along with SLE-like, SSc-like, and RA-like features). The distinction from overlap is subtle	MCTD → each component disease is mild/incomplete; hallmark is high-titre anti-U1 RNP ^[1]. In overlap, each disease is fully expressed
Rheumatoid arthritis (RA)	RA can rarely cause myositis (Rheupus = RA + SLE overlap). More commonly, RA patients have weakness from disuse atrophy, steroid myopathy, or pain-limited effort	RA: morning stiffness > 1 hour, erosive arthritis, anti-CCP positive, rheumatoid nodules ^[12]. True RA-myositis overlap ("Rheupus") has both erosive deforming polyarthritis AND markedly elevated CK with myositis on biopsy

These are important to rule out because they are treatable and can coexist with autoimmune diseases (e.g. hypothyroidism is common in SLE patients):

Condition	Mechanism of Weakness	Key Distinguishing Features
Hypothyroidism ^[9]	Reduced metabolic rate → impaired muscle energy metabolism → myofibre swelling and CK leak. Myopathy associated with hypothyroidism can mimic inflammatory myopathy with a subacute onset of proximal muscle weakness and elevated CK ^[9]	Check TFT! Hypothyroid myopathy has elevated CK but normal or mildly elevated CK (rarely > 10× ULN); sluggish relaxation phase of reflexes (hung-up reflexes); responds to thyroxine replacement
Cushing's syndrome (proximal) ^[13]	Excess glucocorticoids → protein catabolism in type II muscle fibres → proximal weakness and wasting	CK is typically normal (no fibre necrosis); look for Cushingoid features (moon face, striae, buffalo hump). Important: iatrogenic steroid myopathy is the most common cause in rheumatology patients already on prednisolone — this is a classic diagnostic dilemma
Hyperthyroidism (proximal) ^[13]	Accelerated muscle catabolism → wasting and weakness	CK normal or mildly elevated; hyperreflexia (cf. hypothyroid hung-up reflexes); tremor, tachycardia, weight loss
Electrolyte disturbance	Hypokalemia ^[13] → impaired muscle cell membrane depolarisation → weakness (can be acute/episodic). Hypocalcemia → increased neuromuscular excitability → tetany rather than weakness. Hypophosphatemia → impaired ATP synthesis → proximal weakness	Check U&E, Ca, PO₄, Mg. These are rapidly reversible with correction
Metabolic myopathies	Disorders of carbohydrate, lipid and purine metabolism ^[13] → impaired energy production in muscle	Usually presents in childhood/young adulthood; exercise intolerance, second-wind phenomenon (McArdle disease); requires specialised metabolic testing

The Steroid Myopathy Trap

A patient with overlap myositis on high-dose prednisolone who develops worsening weakness poses a classic dilemma: is this a disease flare or steroid myopathy?

Disease flare: CK rises, ESR/CRP rises, EMG shows active myopathic changes
Steroid myopathy: CK is normal, ESR/CRP may be normal, EMG may show non-specific changes or be normal

The approach: check CK. If CK is rising → flare → increase immunosuppression. If CK is normal or falling → likely steroid myopathy → taper steroids.

Drug	Mechanism	Features
Statins (HMG-CoA reductase inhibitors) ^[7]^[13]	Statin-induced myotoxicity → direct myofibre damage (toxic) OR triggering of anti-HMGCR AINM (autoimmune). "HMG-CoA reductase" is the enzyme statins inhibit; the antibody anti-HMGCR targets the same enzyme	Toxic: CK mildly elevated, resolves on stopping statin. AINM: CK markedly elevated, does NOT resolve on stopping statin — needs immunosuppression
Glucocorticoids (proximal) ^[7]^[13]	Type IIb fibre atrophy from protein catabolism — no necrosis, hence CK is normal	Insidious onset; dose-dependent; fluor- inated steroids (dexamethasone) are worst
Colchicine ^[7]	Disrupts microtubule function → vacuolar myopathy	Usually in setting of renal impairment (colchicine accumulates); CK mildly elevated
D-Penicillamine	Can trigger autoimmune myositis (PM-like), SLE-like syndrome, or MG	Penicillamine may trigger Ab-mediated MG reaction ^[3]; may also cause inflammatory myositis
Checkpoint inhibitors (nivolumab, pembrolizumab)	Immune-related adverse event → inflammatory myositis, can be severe with CK markedly elevated and even overlap with MG	Increasingly important in the era of immunotherapy; temporal relationship with checkpoint inhibitor initiation

Condition	Why It May Be Confused	How to Distinguish
Myasthenia gravis (MG) ^[9]	Both present with proximal weakness. MG presents with muscle fatigability but can cause diffuse muscle weakness	Distinguished from myositis by presence of facial muscle weakness, normal muscle enzymes, characteristic EMG changes (decrement on RNS) and AChR antibodies ^[9]. Key: MG has fatigability (worse with use, better with rest); myositis has constant weakness. MG spares CK.
Lambert-Eaton myasthenic syndrome (LEMS)	Proximal weakness, particularly lower limbs	LEMS improves with repeated use (opposite of MG — "inverse fatigability"); associated with SCLC; anti-VGCC antibodies; CK normal; incremental response on RNS

Condition	Why It May Be Confused	How to Distinguish
Muscular dystrophy ^[7]^[9]^[13]	Proximal weakness (e.g. limb-girdle muscular dystrophy, FSHMD). CK can be elevated.	Family history (inherited, usually AD or XR); very slow progression over years/decades; NO autoimmune features; genetic testing is diagnostic
Myotonic dystrophy ^[9]^[13]	Proximal myotonic myopathy (PROMM) presents with myotonia, slowed relaxation following a normal muscle contraction and positive family history ^[9]	Myotonia (delayed relaxation after grip) — not seen in inflammatory myositis; characteristic facies; multisystem involvement (cataracts, cardiac, endocrine); CTG repeat expansion testing

Condition	Mechanism	How to Distinguish
Viral myositis (HIV, CMV, EBV, influenza) ^[7]^[13]	Direct viral invasion of myofibres → necrosis and inflammation	Acute onset often with preceding viral prodrome; CK elevated; resolves as infection clears (usually self-limiting); viral serology positive
Pyomyositis ^[13]	Bacterial infection of muscle (usually S. aureus) → abscess formation within muscle	Focal, painful, swollen muscle (not diffuse symmetrical); fever, leucocytosis; MRI shows focal collection; usually in immunocompromised or tropical settings
Parasitic myositis (trichinosis, toxoplasmosis) ^[13]	Parasitic invasion of myofibres	Travel/exposure history; eosinophilia; specific serology

Condition	Notes
Rhabdomyolysis ^[7]^[13]	Massive muscle necrosis from crush injury, seizures, drugs, extreme exertion → CK markedly elevated (> 10,000 IU/L), myoglobinuria, AKI. Distinguished by acute onset, dark urine, and clear precipitant
Cancer-associated myositis	Not a separate "overlap" but a paraneoplastic phenomenon. 1/3 malignancy (lung, breast, gastric, NPC) — usually diagnosed within 1 year of DM/PM ^[11]. Always screen for malignancy, especially in older patients with new DM
Polymyalgia rheumatica (PMR)	Proximal pain and stiffness (NOT weakness) in > 50y patients with very high ESR/CRP. CK is normal. Responds dramatically to low-dose steroids. PMR does not cause true weakness — the "weakness" is actually pain-limited effort

Feature	Overlap Myositis	Pure DM	Pure PM	IBM	MG	Hypothyroid Myopathy	Steroid Myopathy
Distribution	Proximal, symmetric	Proximal, symmetric	Proximal, symmetric	Distal + proximal	Ocular/bulbar/proximal	Proximal	Proximal
CK	↑↑	↑↑	↑↑	Normal to mild ↑	Normal	Mild ↑	Normal
Skin signs	Variable	Yes (pathognomonic)	No	No	No	Dry skin (hypothyroid)	Cushingoid
Other CTD features	Yes (defining)	No	No	No	May have thymic pathology	No	No
Fatigability	No	No	No	No	Yes	No	No
Response to steroids	Good	Good	Moderate	Poor	N/A	Thyroxine needed	Taper steroids
Reflexes	Preserved	Preserved	Preserved	Preserved	Preserved (no wasting)	Hung-up (delayed)	Preserved
EMG	Myopathic	Myopathic	Myopathic	Mixed myopathic + neurogenic	Decremental RNS	Myopathic	May be normal

High Yield Summary — Differential Diagnosis

Closest differentials: other IIM subtypes (pure DM, pure PM, IBM, AINM, antisynthetase syndrome). The key to overlap myositis is the presence of another well-defined CTD alongside the myositis.
Hypothyroid myopathy is the most important endocrine mimic — always check TFT ^[9].
Steroid myopathy is the most important iatrogenic mimic in a patient already on treatment — CK is normal (no fibre necrosis).
MG is distinguished by fatigability, normal CK, and anti-AChR antibodies ^[9].
IBM is distinguished by insidious onset, distal > proximal pattern, older males, and poor response to treatment ^[9].
Drug-induced myopathy (statins, glucocorticoids, colchicine) must always be considered — check the drug chart ^[7].
Always screen for malignancy in any new inflammatory myositis, especially DM in elderly: NPC is the key malignancy in Hong Kong ^[2]^[3].
MCTD vs overlap: MCTD has mild/incomplete forms of each disease with anti-U1 RNP; overlap has fully expressed discrete diseases ^[1].

Active Recall - Differential Diagnosis of Overlap Myositis

References

^[1] Senior notes: Block A - Syncope and irregular heartbeat (p30) — MCTD vs overlap distinction ^[2] Senior notes: Ryan Ho Rheumatology (p90–92) — PM/DM epidemiology, clinical features, antibody subsets, overlap syndromes, malignancy, prognosis ^[3] Senior notes: Ryan Ho Neurology (p194–195) — Inflammatory myopathies classification, pathology, clinical evaluation ^[7] Lecture slides: Neurology - Two cases of lower limb weakness (p38) — Differential Diagnosis of Myopathy ^[8] Lecture slides: Neurology - Two cases of lower limb weakness (p39) — Dermatomyositis Clinical Presentation ^[9] Senior notes: MBBS Final MB Medicine - Felix PY Lai (p1757) — Differential diagnosis of DM/PM ^[10] Lecture slides: GC 056. Generalized muscle weakness (p36) — Overlap Myositis, Troyanov classification, antisynthetase syndrome ^[11] Senior notes: Maksim Medicine Notes (p320) — IIM classification, CADM, cancer-associated myositis, aetiology ^[12] Senior notes: Ryan Ho Fundamentals (p408) — Polyarthritis differential diagnosis ^[13] Senior notes: MBBS Final MB Pediatrics - Felix PY Lai (p706) — Differential diagnosis of myopathies table

Diagnostic Criteria, Algorithm and Investigations for Overlap Myositis

1. Diagnostic Criteria

Overlap myositis does not have its own standalone classification criteria set in the way that RA or SLE does. Instead, diagnosis rests on two pillars that must both be satisfied:

The patient meets criteria for an idiopathic inflammatory myopathy (IIM)
The patient simultaneously meets criteria (or has unequivocal features) of at least one other well-defined connective tissue disease (CTD)

Therefore, you need to be familiar with the criteria used to diagnose the myositis component and then layer on top the criteria for the overlapping CTD.

1.1 Criteria for the Myositis Component

Bohan and Peter criteria (1975): PM require all of 1–4, DM require any 3 in 1–4 + 5 ^[11]

The five criteria are:

#	Criterion	Explanation (From First Principles)
1	Symmetrical weakness of limb-girdle muscles and anterior neck flexors	The clinical hallmark — inflammatory destruction of proximal muscles produces weakness in the shoulder girdle, pelvic girdle, and neck flexors (SCM, scalenes)
2	Muscle biopsy: typical of myositis	Histological proof of inflammation — necrosis/degeneration/regeneration of muscle fibres + inflammatory infiltrate
3	Muscle enzyme elevation (esp. CK)	Damaged muscle membranes leak CK, LDH, AST, ALT, aldolase into the blood
4	EMG: typical of myositis — spontaneous fibrillation; polyphasic low-amplitude motor unit potential	EMG distinguishes myopathic from neuropathic processes. Fibrillation at rest = denervated fibres; short-duration, low-amplitude, polyphasic potentials = loss of muscle fibres within motor units
5	Cutaneous manifestations of DM: e.g. heliotrope rash, Gottron's papules	The DM-specific rash distinguishes DM from PM

Interpretation:

PM = criteria 1 + 2 + 3 + 4 (all four must be met)
DM = criterion 5 (typical DM rash) + any 3 of criteria 1–4

Limitation of Bohan-Peter for Overlap Myositis

The 1975 Bohan-Peter criteria do NOT specifically address overlap myositis or antibody subsets. They were designed to diagnose PM and DM in isolation. For overlap myositis, you apply Bohan-Peter to confirm myositis, then separately demonstrate the overlapping CTD. This is why newer criteria have been developed.

2017 EULAR/ACR classification criteria for IIM: include age of onset, antibodies (only anti-Jo1 now), different scoring with / without muscle biopsy ^[11]

These are probability-based criteria that calculate a score from weighted variables and yield a probability of having IIM. Key features:

Variable	Score Without Biopsy	Score With Biopsy
Age of onset ≥ 18y vs ≥ 40y	1.3 – 2.1	1.5 – 1.8
Muscle weakness (proximal UL, proximal LL, neck flexors)	0.7 – 1.3 each	0.7 – 1.2 each
Skin manifestation (heliotrope, Gottron's papules, Gottron's sign)	3.1 – 3.7	3.2 – 3.6
Anti-Jo-1 antibody positive	3.9	2.7
Dysphagia	0.7	0.6
Elevated CK or aldolase	1.3	1.4
Muscle biopsy features	N/A	1.7 (endomysial infiltrate), 1.9 (perifascicular atrophy)

A total score ≥ 5.5 (without biopsy) or ≥ 6.7 (with biopsy) = "probable IIM" (sensitivity ~87%, specificity ~82%). Scores ≥ 7.5 / ≥ 8.7 = "definite IIM".

Why this matters for overlap myositis: The 2017 criteria explicitly include anti-Jo-1 (the most common antisynthetase antibody), which is heavily weighted. Since antisynthetase syndrome often presents as overlap myositis, this criterion directly captures a large proportion of overlap cases. However, other MSAs (anti-Mi-2, anti-MDA5, anti-SRP, etc.) are NOT yet included in the scoring — a known limitation.

Once myositis is established, you must separately demonstrate the second disease. Each CTD has its own established criteria:

CTD	Criteria Set	Key Requirements
SLE	2019 EULAR/ACR SLE criteria	ANA ≥ 1:80 as entry criterion + additive scoring across 7 clinical and 3 immunological domains (score ≥ 10)
SSc	2013 ACR/EULAR SSc criteria	Skin thickening of fingers extending proximal to MCPJs (sufficient alone, score 9); or additive scoring including sclerodactyly, Raynaud's, SSc-specific antibodies, etc. (score ≥ 9)
RA	2010 ACR/EULAR RA criteria	Joint involvement + serology (RF/anti-CCP) + acute phase reactants + duration ≥ 6 weeks (score ≥ 6/10)
Sjögren syndrome	2016 ACR/EULAR SS criteria	Focus score ≥ 1 on labial salivary gland biopsy, anti-Ro/SSA, ocular staining score, Schirmer test, salivary flow rate (score ≥ 4)
MCTD	Various (Alarcon-Segovia, Sharp, Kasukawa)	High-titre anti-U1 RNP + features of ≥ 2 of SLE/SSc/PM

3. Investigation Modalities — Detailed Guide

The investigations for overlap myositis serve four purposes:

Confirm myositis (muscle enzymes, EMG, biopsy)
Subtype the IIM and identify the overlap (autoantibodies)
Assess organ involvement (lungs, heart, oesophagus)
Screen for malignancy (especially DM component in elderly)

3.1 Blood Tests

Raised creatine kinase ^[8]

Enzyme	What It Tells You	Expected Findings in Overlap Myositis
Creatine kinase (CK)	The most sensitive and specific blood marker of muscle damage. CK is released when the sarcolemma (muscle cell membrane) is disrupted by inflammation/necrosis	Rarely normal (~5%), usually > 10× ULN, may even be > 50–100× ULN in severe cases ^[2]. In the GC Rheum interactive tutorial case: serum creatine kinase 1570 U/L (NR 22–198) ^[14]
LDH	Less specific (also from liver, RBCs, etc.), but useful as adjunct	Elevated in active myositis
AST and ALT	Traditionally "liver enzymes" but ALSO released from damaged muscle. This is a common exam trap	Elevated muscle enzymes: CK, LDH, AST, ALT ^[2]. Always check CK before attributing raised AST/ALT to "liver disease" in a myositis patient
Aldolase	Enzyme in glycolytic pathway; released from damaged muscle; sometimes elevated when CK is normal (rare)	Included in Bohan-Peter criteria and EULAR/ACR 2017 criteria

CK values: 200–1000 IU/L: most myopathies, SMA/MND, rigorous exercise, IM injection, after EMG/muscle biopsy, tonic-clonic seizures, statin/neuroleptic-induced. 1000–10000 IU/L: inflammatory myopathies, acute rhabdomyolysis, DMD/BMD ^[3]

AST/ALT Trap

A patient with overlap myositis may have elevated AST and ALT that are misinterpreted as liver disease. Always check CK simultaneously. If CK is markedly elevated, the transaminase elevation is likely from muscle, not liver. This mistake can lead to unnecessary liver investigations and delayed myositis treatment.

Marker	Expected Findings	Interpretation
ESR	↑↑ ^[2]	Non-specific marker of systemic inflammation; typically elevated in active myositis
CRP	↑↑ ^[2]	Same as above. Note: in pure SLE, CRP may be normal/mildly elevated unless there is serositis or infection — but in overlap myositis the myositis component usually drives CRP up

Test	Why	What to Look For
CBC	Screen for cytopenias (SLE overlap → lymphopenia, thrombocytopenia), anaemia of chronic disease	Leucopenia, lymphopenia suggest SLE overlap
L/RFT	Renal involvement (lupus nephritis), baseline before immunosuppression	Proteinuria, elevated creatinine in SLE overlap
TFT	Rule out thyroid myopathy ^[2]^[3]^[11]	Hypothyroid myopathy mimics inflammatory myositis — always exclude
Urinalysis	Screen for lupus nephritis, myoglobinuria	Proteinuria, haematuria (lupus nephritis); dark urine with positive dipstick for "blood" but no RBCs on microscopy (myoglobinuria)

Test	Why	Interpretation
CK-MB	Increased in regenerating skeletal muscle affected by the inflammatory response OR involvement of myocardium by myositis ^[5]	Elevated CK-MB in myositis does NOT necessarily mean MI — it can come from regenerating skeletal muscle
cTnI / cTnT	Determine elevated CK is due to muscle or cardiac causes ^[5]	Troponin I is more specific to myocardium; if elevated, consider myocarditis as a complication

3.2 Autoantibodies — The Serological Key to Subtyping

Autoantibodies are the single most important investigation for classifying the IIM subtype and identifying the overlap component. They define clinical phenotype, predict organ involvement, and guide prognosis.

Autoantibodies: Anti-Mi2, anti-NXP2, anti-TIF1, anti-Jo1 (associated with interstitial lung disease) ^[8]

Myositis-specific autoAb: found exclusively in IIM, correlate with genotype and clinical manifestations ^[11]

Antibody	Clinical Association	Overlap Relevance	Prognosis
Anti-Jo-1	Anti-synthetase syndrome: acute myopathy, fever, ILD, polyarthritis, Raynaud's, mechanic's hand ^[10]	Often classified as overlap myositis. Anti-Jo1 antibody positive in GC Rheum case ^[14]^[15]	ILD is the major prognostic determinant
Anti-PL-7, anti-PL-12, anti-OJ, anti-KS, anti-EJ, anti-Zo, anti-Ha-YRS	Other antisynthetase antibodies	Anti-PL-7, anti-PL-12 (amyopathic variant) ^[10]	Similar to anti-Jo-1 but may have more ILD and less myositis
Anti-Mi-2	DM, good response to treatment ^[11]	Low overlap tendency	Good prognosis
Anti-MDA5	CADM with rapidly progressive ILD, skin rash, poor prognosis ^[11]	Moderate (can overlap with SLE features)	Poor prognosis — high mortality from ILD
Anti-TIF1	DM, strongly associated with malignancy (50%), severe skin rash, less ILD, poor prognosis ^[4]^[11]	Low	Must screen for malignancy aggressively
Anti-NXP2	Severe weakness and rash, calcinosis ^[11]	Low	Also high association with malignancy ^[4]
Anti-SRP	IMNM, no rash ^[11]	Low	Refractory to steroids
Anti-HMGCR	Association with statin-induced IMNM ^[11]	Low	May respond to stopping statin + immunosuppression
Anti-SAE	DM, dark skin discolouration ^[11]	Low	Variable

Myositis-associated autoAb: found in IIM patients with features of other CTD ^[11]

Antibody	Overlap CTD	Clinical Significance
Anti-PM/Scl	Overlap with scleroderma ^[10]^[11]	The hallmark antibody of SSc-myositis overlap; associated with mechanic's hands, ILD, protracted course
Anti-Ku	Overlap with scleroderma ^[11]	SSc or SLE overlap
Anti-U1RNP	SLE/MCTD-overlap myositis ^[10]^[11]	High-titre → MCTD; lower titre → SLE overlap
Anti-U3RNP	SSc-overlap myositis ^[10]	Specifically associated with SSc overlap, PAH
Anti-Ro/SSA, Anti-La/SSB	Sjögren syndrome, SLE	Sicca symptoms; may modify ILD risk
Anti-Sm	SLE	Highly specific for SLE

Antibody	CTD	Significance
Anti-dsDNA	SLE	Highly specific; correlates with disease activity and nephritis
Anti-CCP	RA	Highly specific for RA; if positive with erosive arthritis → Rheupus overlap
Anti-Scl-70 (anti-topoisomerase I)	Diffuse cutaneous SSc	ILD risk
Anti-centromere	Limited cutaneous SSc	PAH risk
Anti-RNA polymerase III	SSc	Scleroderma renal crisis risk, malignancy association

Electromyography: myopathic pattern ^[8]

EMG is a neurophysiological study that measures the electrical activity of muscles. It serves two critical purposes:

Confirms myopathy (distinguishes from neuropathy and NMJ disorders)
Identifies active inflammation (fibrillation potentials indicate ongoing muscle membrane instability)

EMG Findings in Inflammatory Myositis — The Classic Triad

EMG: triad of findings ^[2]:

Spontaneous fibrillation potentials at rest

Polyphasic or short duration potentials on voluntary contraction

Salvos of repetitive potentials on mechanical stimulation of nerve

EMG Finding	What It Means (First Principles)
Spontaneous fibrillation potentials at rest	Fibrillation = spontaneous firing of individual muscle fibres that have lost their normal nerve input or whose membrane is irritable from inflammation. In myositis, inflammation disrupts the muscle fibre membrane → spontaneous depolarisation
Low amplitude, short duration, polyphasic motor unit potentials (MUPs)	In a normal motor unit, many muscle fibres fire synchronously → large, uniform potential. In myositis, muscle fibres are destroyed → fewer fibres per motor unit → smaller amplitude + shorter duration. The surviving fibres fire asynchronously → polyphasic
Complex repetitive discharges	Groups of muscle fibres fire in a repetitive, synchronized fashion — reflects chronicity and membrane instability
Increased insertional activity	Needle insertion causes more electrical activity than normal because inflamed muscle membranes are hyperexcitable

From the GC Rheum interactive tutorial: Electromyography shows low amplitude motor-unit potentials with occasional fibrillation potentials, compatible with inflammatory myopathy ^[14]^[15]

EMG — Myopathic vs Neuropathic Pattern

Feature	Myopathic (myositis)	Neuropathic (e.g. GBS, CIDP)
MUP amplitude	Low (fewer fibres per unit)	High (reinnervation → larger units)
MUP duration	Short	Long
Recruitment	Early (many small units recruited quickly to compensate)	Reduced (fewer units available)
Fibrillation	Present (active inflammation)	Present (denervation)
Nerve conduction	Normal	Abnormal (slow velocity, conduction block)

3.4 Muscle Biopsy — The Definitive Investigation

Muscle biopsy: definitive diagnosis ^[5]^[8]

IIM Subtype	Biopsy Findings	Pathophysiological Basis
PM	Endomysial lymphocytic infiltrates (CD8+ T cells); inflammatory cells invading individual muscle fibres; NO signs of vasculopathy ^[2]^[5]	Direct T-cell mediated cytotoxicity against muscle fibres expressing aberrant MHC-I
DM	Perimysial/perivascular infiltrates (B cells, plasmacytoid dendritic cells); perifascicular atrophy; signs of vasculopathy or immune complex deposition ^[2]^[5]	Complement-mediated microangiopathy → capillary dropout → ischaemia at fascicle periphery
IBM	Rimmed vacuoles, inclusion bodies (amyloid deposits), endomysial inflammation	Mixed inflammatory + degenerative process
AINM	Prominent myofibre necrosis with minimal inflammatory infiltrate	Antibody-mediated (anti-SRP / anti-HMGCR) direct myofibre destruction
Overlap myositis	Heterogeneous or non-specific muscle histology ^[10]	Mixed features depending on which IIM subtype and which CTD are overlapping

GC High Yield — Overlap Myositis Histology

The GC 056 lecture slide specifically states that overlap myositis has "heterogeneous or non-specific muscle histology" ^[10]. This means you cannot always make a clear PM vs DM distinction on biopsy in overlap cases — the histology may show mixed features. The autoantibody profile becomes even more important for classification.

MRI: muscle inflammation / necrosis ^[8]

MRI Sequence	Findings	Interpretation
T2W / STIR	Patchy increased T2 signal indicating inflammation and oedema ^[2]	Active myositis — T2 hyperintensity reflects increased water content from inflammation
T1W	Fatty replacement of muscle (in chronic disease)	Irreversible fibrotic/atrophic change
Post-gadolinium T1W	Enhancement in areas of active inflammation	Helps distinguish active inflammation from chronic damage

Why MRI is useful:

Non-invasive alternative to EMG for localising active disease
Guides biopsy site: shows which muscle is actively inflamed → avoids sampling error
Assess large areas of muscle and thus avoid problems with sampling error in muscle biopsy ^[5]
MRI: sensitive but non-specific; D/dx includes muscular dystrophy, metabolic, rhabdomyolysis ^[2]

3.7 Pulmonary Assessment — ILD Screening

ILD is the major driver of morbidity and mortality in overlap myositis, especially with antisynthetase antibodies or anti-MDA5.

Investigations of interstitial lung disease ^[15]

From the GC Rheum interactive tutorial: Pulmonary function test shows a reduced forced vital capacity of 70% predicted and diffusion capacity of the lungs for carbon monoxide (DLCO) of 64% predicted ^[14]^[15]

Parameter	Expected in ILD	Explanation
FVC ↓	Restrictive pattern	Fibrotic/inflamed lungs cannot expand fully → reduced total volume
TLC ↓	Restrictive pattern	Same mechanism
FEV₁/FVC ratio	Normal or ↑ ^[16]	Both FEV₁ and FVC decrease proportionally (unlike obstructive disease where FEV₁ falls more)
DLCO ↓	Impaired gas exchange	Thickened alveolar-capillary membrane from inflammation/fibrosis → reduced CO diffusion

High-resolution CT scan of the thorax reveals ground glass opacities predominantly over the lower lobes. There was no honeycombing ^[14]^[15]

HRCT Pattern	ILD Subtype	Clinical Correlation
GGO (ground glass opacities) ± reticular changes, bibasal, sparing subpleural region	NSIP (non-specific interstitial pneumonia)	The most common ILD pattern in CTD-associated/overlap myositis ^[16]
Peripheral/subpleural honeycombing + traction bronchiectasis	UIP (usual interstitial pneumonia)	More common in IPF; less common in myositis
Consolidation with air bronchograms	COP (cryptogenic organising pneumonia)	May occur in myositis-associated ILD
Diffuse GGO ± consolidation, rapidly progressive	DAD (diffuse alveolar damage)	Anti-MDA5 associated rapidly progressive ILD — very poor prognosis

Investigation	Why	Key Findings
ECG	Screen for conduction abnormalities, arrhythmias from myocardial inflammation	AV blocks, bundle branch blocks, ST/T changes
Echocardiography	Assess ventricular function, pericardial effusion, pulmonary hypertension	↓EF (myocarditis), pericardial effusion, ↑RVSP (PAH from ILD or SSc)

Potential association between cancer and dermatomyositis and the rationale of cancer screening ^[15]

Investigations to rule out malignancy: Refer ENT (NPC), Gynae (CA cervix), GI (upper and lower endoscopy) ^[11]

Investigation	Target Malignancy	Rationale
ENT referral	NPC (nasopharyngeal carcinoma)	Important in this locality (Hong Kong) ^[3]
Gynaecology referral	CA cervix, CA ovary	Pap smear, pelvic USS, CA-125
GI endoscopy (upper + lower)	Gastric cancer, colorectal cancer	OGD + colonoscopy
Mammography	Breast cancer	Standard screening
CT thorax/abdomen/pelvis	Lung, pancreatic, bladder cancers	Included in staging workup
PET-CT	Occult malignancy	Indication of PET scan: occult malignancy, occult infection ^[1]; useful when standard screens are negative but clinical suspicion remains high
Tumour markers	Various	CEA, CA 19-9, CA-125, AFP, PSA — limited sensitivity/specificity but adjunctive

GC High Yield — Malignancy Screening Rationale

The GC Rheum interactive tutorial (Case 2) lists cancer screening as a key learning objective ^[15]. In any new diagnosis of DM (or overlap myositis with DM features), especially in patients > 40 years, a thorough malignancy screen must be performed. The temporal relationship is important: malignancy can be diagnosed before, with, or after onset of dermatomyositis ^[3]. Repeat screening annually for at least 3 years is recommended.

Overlap CTD	Specific Investigations
SLE	Anti-dsDNA, complement C3/C4, urinalysis with urine protein/creatinine ratio, renal biopsy if nephritis suspected
SSc	Nailfold capillaroscopy, anti-Scl-70/anti-centromere/anti-RNA pol III, HRCT for ILD, echocardiography for PAH, Rodnan skin score (assessment of skin tightening as proxy for disease activity) ^[1]
RA	RF, anti-CCP, X-ray hands/feet for erosions, USG joints (can detect subclinical inflammation, allow for more aggressive treatment) ^[1]
Sjögren	Schirmer test, salivary gland biopsy (focus score), anti-Ro/SSA and anti-La/SSB

Category	Investigations
Confirm myositis	CK (+LDH, AST, ALT, aldolase), EMG, muscle biopsy (± MRI-guided), MRI skeletal muscles
Subtype and antibodies	ANA, anti-ENA panel, myositis-specific Ab panel (anti-Jo-1, anti-Mi-2, anti-MDA5, anti-TIF1γ, anti-NXP2, anti-SRP, anti-HMGCR, anti-SAE), myositis-associated Ab (anti-PM/Scl, anti-Ku, anti-U1RNP, anti-U3RNP, anti-Ro, anti-La, anti-Sm)
Screen for CTD overlap	Anti-dsDNA, C3/C4 (SLE); anti-Scl-70, anti-centromere (SSc); RF, anti-CCP (RA); anti-Ro/SSA, anti-La/SSB (SS); nailfold capillaroscopy
Assess organ involvement	PFT (FVC, DLCO), HRCT thorax, ECG, echocardiography, speech therapist assessment, urinalysis
Rule out mimics	TFT (hypothyroid), U&E (electrolytes), drug history review (statins, steroids)
Malignancy screen	ENT (NPC), gynaecology, GI endoscopy, mammography, CT TAP ± PET-CT, tumour markers
Baseline before treatment	HBV/HCV serology (HK: high HBV prevalence — mandatory before immunosuppression), IGRA/CXR (TB screen), bone density (if starting steroids)

High Yield Summary — Diagnostic Criteria, Algorithm and Investigations

Bohan-Peter criteria (1975): PM = all 4 of proximal weakness + elevated CK + myopathic EMG + positive biopsy. DM = typical rash + any 3 of the 4. Still the most examined criteria.
2017 EULAR/ACR criteria: Probability-based scoring; includes anti-Jo-1 (heavily weighted at 3.9 points without biopsy).
Troyanov classification (GC 056): Overlap myositis = myositis + overlap features (other than rash) and/or overlap autoAb (anti-U1RNP, anti-PM/Scl, anti-Ku, anti-U3RNP). Antisynthetase syndrome is included.
"2 out of 3" practical rule: elevated CK + myopathic EMG + positive muscle biopsy — need 2 of 3 to confirm myositis.
Overlap myositis has heterogeneous or non-specific muscle histology — autoantibodies are especially important for classification.
Key investigations: CK (most sensitive muscle marker), EMG (myopathic pattern), muscle biopsy (definitive), autoantibodies (classification + prognosis), HRCT + PFT (ILD), malignancy screening (mandatory in DM, especially NPC in HK).
Always check TFT to exclude hypothyroid myopathy and review drug chart for statin/steroid myopathy.
Always screen for HBV before immunosuppression in Hong Kong.

Active Recall - Diagnosis and Investigations of Overlap Myositis

References

^[1] Senior notes: Block A - Syncope and irregular heartbeat (p30) — MCTD vs overlap distinction, PET scan indications, Rodnan skin score, joint investigation modalities ^[2] Senior notes: Ryan Ho Rheumatology (p92) — Diagnosis of myositis (2 out of 3 rule), CK values, EMG triad, muscle biopsy, autoantibodies, MRI, skin biopsy ^[3] Senior notes: Ryan Ho Neurology (p191, p194–195) — CK ranges, investigations for muscle diseases, inflammatory myopathies classification, malignancy association ^[4] Senior notes: Block A - Dermatology PBL 2 (p7) — Anti-TIF1γ and anti-NXP2 malignancy association ^[5] Senior notes: MBBS Final MB Medicine - Felix PY Lai (p1758, p1760) — Bohan-Peter criteria, biochemical tests, cardiac enzymes, muscle biopsy technique and histopathology, skin biopsy, EMG, MRI, CXR ^[8] Lecture slides: Neurology - Two cases of lower limb weakness (p40) — DM investigations (CK, autoantibodies, EMG, MRI, muscle biopsy, malignancy screen) ^[10] Lecture slides: GC 056. Generalized muscle weakness (p36) — Overlap Myositis Troyanov classification, antisynthetase syndrome, overlap autoantibodies ^[11] Senior notes: Maksim Medicine Notes (p320–321) — Bohan-Peter criteria, 2017 EULAR/ACR criteria, MSA and MAA panels, malignancy screening investigations ^[13] Senior notes: MBBS Final MB Pediatrics - Felix PY Lai (p709) — Autoantibodies table (general, MSA, MAA, cancer-associated), EMG findings, ANA ^[14] Senior notes: Block A - Rheumatology Interactive Tutorial (p3) — GC Rheum Case 2 clinical scenario (CK, ANA, CXR, PFT, EMG, HRCT, anti-Jo1, speech therapy) ^[15] Lecture slides: GC Interactive tutorial Rheum case 2 student copy (p1, p6) — Learning objectives, further investigation findings (anti-Jo1, PFT, EMG, HRCT) ^[16] Senior notes: Ryan Ho Respiratory (p121–123) — ILD investigation approach (PFT, HRCT patterns, BAL, lung biopsy), NSIP, IPF

Management of Overlap Myositis

Non-pharmacological: bed rest in acute attacks, sun protection, physiotherapy to prevent contracture, IV fluids (rhabdomyolysis prophylaxis), stop statins ^[11]

Measure	Rationale (From First Principles)	Details
Bed rest in acute attacks	Exercising actively inflamed muscles can worsen fibre necrosis and delay recovery. Rest allows the inflammation to be controlled by medication first	Short-term only during acute flares; prolonged bed rest causes deconditioning and worsens long-term outcomes
Sun protection	DM skin manifestations are photosensitive — UV light upregulates MHC-I expression on keratinocytes and activates complement in dermal capillaries, worsening the rash	Broad-spectrum sunscreen (SPF ≥ 50), protective clothing, avoid peak UV hours. Important even in overlap myositis with DM features
Physiotherapy to prevent contracture	Chronic inflammation → fibrosis and shortening of muscle fibres → joint contractures if not actively prevented. Physical therapy preserves range of motion and prevents deconditioning	Gentle passive/active-assisted range of motion exercises during acute phase; progressive resistance training during remission. PT should be supervised to avoid over-exertion
IV fluids (rhabdomyolysis prophylaxis)	Severe myositis with very high CK (> 10,000 IU/L) → myoglobin released → deposits in renal tubules → acute kidney injury. IV normal saline dilutes myoglobin and maintains tubular flow	Target urine output > 200 mL/hour in severe cases. Alkalinisation of urine (with IV sodium bicarbonate) may reduce myoglobin precipitation but is debated
Stop statins	Statins (HMG-CoA reductase inhibitors) can cause direct toxic myopathy or trigger anti-HMGCR autoimmune necrotising myopathy	Always review drug chart on admission. Even if statins are not the primary cause, they may be exacerbating the myopathy
Speech therapy assessment	Dysphagia from pharyngeal/oesophageal striated muscle weakness → aspiration risk	Videofluoroscopy-guided dietary modification (texture-modified diet, thickened fluids). NG tube or PEG if severe
Occupational therapy	Functional aids for ADLs compromised by proximal weakness	Raised toilet seats, grab rails, adapted cutlery

2. First-Line Pharmacological Therapy — Induction

Initial treatment: Oral prednisolone ^[17] High-dose steroid (PO prednisolone 1 mg/kg/day): prolonged therapy until active disease controlled for 1 year ^[11]

Aspect	Details
Drug	Oral prednisolone — "prednisolone" breaks down to pred- (a synthetic corticosteroid) + -nisolone (a modified pregnane steroid). It suppresses the immune system broadly by inhibiting NF-κB transcription factor → ↓pro-inflammatory cytokines (IL-1, IL-6, TNF-α), ↓T-cell activation, ↓B-cell antibody production
Dose	1 mg/kg/day ^[2]^[11], typically 40–60 mg/day for an average adult
Duration	Maintain high dose for 4–6 weeks (or until CK normalises and strength improves), then begin gradual taper
Taper	Reduce by ~10 mg every 2 weeks initially, then slower reductions (5 mg → 2.5 mg decrements) once below 20 mg/day. Aim to reach a maintenance dose of ≤ 7.5–10 mg/day or off entirely if possible
Monitoring	CK levels (should fall with effective treatment — CK normalisation typically precedes clinical strength improvement by weeks), clinical muscle strength (MRC grading), inflammatory markers

For severe or fulminant cases (e.g. rapidly progressive ILD with anti-MDA5, severe dysphagia, respiratory muscle weakness):

Severe / refractory cases: IV methylprednisolone ^[17]

Drug	Dose	Rationale
IV methylprednisolone pulse	500–1000 mg/day for 3–5 days	"Pulse" therapy delivers a massive bolus of glucocorticoid to rapidly suppress overwhelming inflammation when oral therapy is too slow. Methylprednisolone has less mineralocorticoid effect than prednisolone → less fluid retention

Steroid sparing agents: azathioprine, mycophenolate mofetil ^[17] Steroid-sparing agents: initiated with steroids to decrease steroid dose and side effects ^[11]

Why start these early? Glucocorticoids are effective but have devastating long-term side effects (osteoporosis, diabetes, Cushing's syndrome, immunosuppression, cataracts, AVN). Steroid-sparing agents allow you to taper steroids to the lowest effective dose while maintaining disease control.

Agent	Mechanism	Dose	Onset	Key Side Effects	Specific Precautions
Azathioprine ^[2]^[11]^[17]	Purine analogue → inhibits DNA synthesis in rapidly dividing lymphocytes → ↓T and B cell proliferation. Metabolised to 6-mercaptopurine (6-MP), then to active 6-thioguanine nucleotides (6-TGN)	1–3 mg/kg/day	Delayed onset ~3 months ^[18]	Bone marrow suppression, allergy, hepatotoxicity, pancreatitis ^[18]	Must check TPMT and NUDT15 enzyme activity before starting ^[18]. Deficiency → excessive accumulation of toxic metabolites → severe myelosuppression. Also check if patient is on xanthine oxidase inhibitors (allopurinol, febuxostat) → blocks alternative metabolism pathway → toxicity ^[18]
Methotrexate (MTX) ^[2]^[11]	Folate antagonist → inhibits dihydrofolate reductase → ↓purine/pyrimidine synthesis → ↓lymphocyte proliferation. At low doses, also inhibits AICAR transformylase → ↑adenosine → anti-inflammatory	7.5–25 mg/week (oral or SC)	4–8 weeks	Hepatotoxicity, myelosuppression, pneumonitis (MTX lung — hypersensitivity reaction), teratogenicity, oral ulcers	Supplement with folic acid 5 mg weekly (given 48h after MTX) to reduce side effects. Contraindicated in pregnancy. Monitor LFT, CBC. Avoid in significant renal impairment (MTX is renally cleared)
Mycophenolate mofetil (MMF) ^[2]^[17]	Inhibits inosine monophosphate dehydrogenase (IMPDH) → blocks de novo purine synthesis in lymphocytes (lymphocytes are uniquely dependent on this pathway, unlike other cells which can use salvage pathway) → selective lymphocyte suppression	1–3 g/day in divided doses	4–8 weeks	GI upset (nausea, diarrhoea), myelosuppression, teratogenicity	Increasingly used as first-line steroid-sparing agent in myositis-ILD (NSIP pattern). Contraindicated in pregnancy

GC High Yield — Azathioprine Pharmacogenomics

Before starting azathioprine, always check:

TPMT enzyme activity → converts active 6-MP into inactive 6-MMP
NUDT15 enzyme activity → prevents excessive accumulation of toxic 6-TGTP (more common in Hong Kong population ^[18])
Concomitant xanthine oxidase inhibitors (allopurinol, febuxostat) → XO is crucial for conversion of active 6-MP into inactive 6-thiouric acid; blocking this pathway = accumulation = toxicity ^[18]

This is a pharmacogenomics concept frequently examined in HKUMed papers.

If the patient fails to respond to high-dose steroids + a steroid-sparing agent within 3–6 months, or presents with severe/life-threatening disease, escalation is needed:

Severe / refractory cases: IV methylprednisolone, Intravenous immunoglobulin, Rituximab ^[17] IVIG for refractory disease ^[2] Anti-CD20 (still experimental) ^[2]

Agent	Mechanism (From First Principles)	Indication	Dose/Protocol	Key Considerations
IVIG (Intravenous immunoglobulin) ^[2]^[11]^[17]	Pooled human IgG from thousands of donors → multiple mechanisms: (1) Fc-mediated blockade of activating Fc receptors on macrophages → ↓phagocytosis of opsonised cells; (2) Neutralisation of pathogenic autoantibodies; (3) Modulation of complement activation; (4) Expansion of regulatory T cells	Severe or refractory myositis ^[11]; rapid-onset option while waiting for steroid-sparing agents to take effect; particularly useful for DM skin disease refractory to steroids	2 g/kg divided over 2–5 days, repeated monthly for 3–6 cycles	Expensive; risk of headache, aseptic meningitis, anaphylaxis (especially in IgA-deficient patients), thromboembolic events, renal impairment. Check IgA levels before first dose
Rituximab (anti-CD20) ^[2]^[17]	Chimeric monoclonal antibody targeting CD20 on B lymphocytes → B-cell depletion via ADCC, CDC, and direct apoptosis → ↓autoantibody production, ↓antigen presentation by B cells	Refractory myositis (especially anti-synthetase syndrome, anti-SRP AINM); overlap myositis with SLE features	1000 mg IV × 2 doses (days 0 and 14), repeated every 6 months	Screen for HBV (risk of reactivation → fatal fulminant hepatitis; mandatory in HK given high HBV prevalence), screen for TB. Progressive multifocal leukoencephalopathy (PML) is a rare but serious risk. Hypogammaglobulinaemia with prolonged use
Cyclophosphamide ^[2]	Alkylating agent → cross-links DNA → kills rapidly dividing cells including lymphocytes → potent immunosuppression	ILD associated with myositis (especially rapidly progressive ILD with anti-MDA5); severe organ-threatening disease (e.g. lupus nephritis in SLE-overlap)	IV pulse: 500–1000 mg/m² monthly × 6 months (Euro-Lupus protocol uses lower doses)	Gonadal toxicity (offer fertility preservation), haemorrhagic cystitis (give MESNA prophylaxis), myelosuppression, secondary malignancy (bladder cancer), infection risk
Calcineurin inhibitors (tacrolimus, ciclosporin) ^[3]	Tacrolimus inhibits calcineurin → blocks NFAT signalling → ↓IL-2 transcription → ↓T-cell activation. Ciclosporin works similarly via cyclophilin binding	DM/PM refractory to conventional therapy; particularly useful in anti-MDA5 rapidly progressive ILD (Japanese/East Asian protocols combine tacrolimus + IV cyclophosphamide + steroids)	Tacrolimus: 0.05–0.1 mg/kg/day (target trough 5–10 ng/mL). Ciclosporin: 2–5 mg/kg/day	Nephrotoxicity (monitor creatinine and drug levels), hypertension, hyperglycaemia, tremor, gingival hypertrophy (ciclosporin)
Plasmapheresis ^[3]	Physical removal of circulating autoantibodies and immune complexes from plasma → rapid reduction in pathogenic antibody titre	Acute life-threatening myositis (e.g. respiratory failure), bridge therapy while immunosuppressants take effect	5–7 exchanges over 2 weeks	Temporary effect — antibodies will return unless immunosuppression is established. Risk of hypotension, catheter-related infection, coagulopathy

4. Organ-Specific Management

ILD is the principal driver of morbidity and mortality in overlap myositis, especially with antisynthetase or anti-MDA5 antibodies.

Lung fibrosis: high dose steroids + immunosuppressants ^[2]

Severity	Management	Rationale
Mild stable ILD	Steroids + azathioprine or MMF; monitor with serial PFT (FVC, DLCO) every 3–6 months	NSIP pattern (the commonest CTD-ILD pattern) is often responsive to immunosuppression
Moderate progressive ILD	Steroids + MMF or cyclophosphamide; consider rituximab	Cyclophosphamide is more potent for progressive fibrotic disease
Rapidly progressive ILD (anti-MDA5)	IV methylprednisolone pulse + IV cyclophosphamide + tacrolimus (triple combination therapy)	This is the most aggressive ILD phenotype with mortality > 50% at 6 months if untreated. East Asian protocols combine all three for maximum immunosuppression
Progressive fibrotic ILD despite immunosuppression	Antifibrotics (nintedanib) — now approved for progressive fibrosing ILD beyond IPF, including CTD-associated ILD ^[16]	Nintedanib inhibits multiple tyrosine kinases (VEGFR, FGFR, PDGFR) → ↓fibroblast proliferation, migration, and collagen deposition. Does not cure but slows decline in FVC
End-stage ILD	Long-term O₂ if PaO₂ < 55 mmHg or SaO₂ < 88% ^[16]; consider lung transplant referral ^[16]	Supportive care for irreversible fibrosis

Cutaneous involvement: moderate to high dose steroid + immunosuppressants; hydroxychloroquine; topical steroids; vasodilators for Raynaud's ^[2]

Treatment	Mechanism	Notes
Hydroxychloroquine (HCQ) ^[2]^[11]	Accumulates in lysosomes → inhibits antigen processing/presentation → ↓autoimmune activation. Also has photoprotective properties	Only effective for skin disease ^[11] — does not treat the myositis component. Dose: 200–400 mg/day. Must screen for retinal toxicity (annual ophthalmology review after 5 years)
Topical corticosteroids	Local anti-inflammatory effect on dermal capillaritis	Moderate potency (e.g. betamethasone valerate) for body; low potency (e.g. hydrocortisone) for face
Sun protection	Prevents UV-triggered disease flare	Already discussed in non-pharmacological section

Supportive (for late bulbar S/S): PT, speech therapy, PEG tube ^[2]

Measure	Details
Speech therapy	Swallowing assessment, texture-modified diet, swallowing exercises
NG tube / PEG tube	If severe dysphagia with aspiration risk and inadequate oral intake
Aggressive immunosuppression	Bulbar involvement indicates severe disease → escalate to IVIG, rituximab, or cyclophosphamide

Vasodilators for Raynaud's ^[2]

Agent	Mechanism
Calcium channel blockers (nifedipine, amlodipine)	Block L-type Ca²⁺ channels in vascular smooth muscle → vasodilatation → improved digital perfusion
PDE5 inhibitors (sildenafil, tadalafil)	Inhibit phosphodiesterase-5 → ↑cGMP → smooth muscle relaxation → vasodilatation
IV iloprost (for severe/refractory)	Prostacyclin analogue → vasodilatation + platelet inhibition → used for critical digital ischaemia
Non-pharmacological	Avoid cold exposure, stop smoking, keep hands warm, avoid beta-blockers

Polyarthritis: NSAIDs ^[2]

Agent	When
NSAIDs	Mild arthralgia — symptomatic relief only. Use with caution (GI bleeding, renal toxicity)
HCQ	First-line DMARD for SLE-associated arthritis; also useful in overlap
MTX	If erosive arthritis (RA overlap)
Biologic DMARDs	If refractory RA overlap — consider TNF inhibitors (but use with caution in myositis as data are limited)

Overlap CTD	Specific Management Considerations
SLE overlap	HCQ for all SLE patients (reduces flares, thrombosis, mortality). Lupus nephritis → MMF or cyclophosphamide induction, then MMF or azathioprine maintenance. Anti-dsDNA and complement monitoring
SSc overlap	ACEi for scleroderma renal crisis (NOT ARBs). Nintedanib/MMF for SSc-ILD. Treat PAH with endothelin receptor antagonists (bosentan), PDE5i, prostanoids. Skin: no proven disease-modifying therapy; MTX may help early dcSSc
Sjögren overlap	Artificial tears, saliva substitutes, pilocarpine for severe sicca. HCQ for fatigue/arthralgia. Rituximab for severe systemic manifestations

Parameter	Frequency	Purpose
CK	Every 2–4 weeks during induction, then every 1–3 months	Tracks disease activity; CK normalisation typically precedes clinical improvement
Clinical muscle strength (MRC scale)	Every visit	Objective measure of response; important because CK can normalise while weakness persists (fibrotic damage)
PFT (FVC, DLCO)	Every 3–6 months if ILD present	Regular F/U lung function tests ^[16]. Declining FVC/DLCO indicates progressive ILD despite treatment → escalate
Inflammatory markers (ESR, CRP)	Every 1–3 months	General disease activity
CBC, LFT, RFT	Every 1–3 months	Monitor for drug toxicity (myelosuppression from azathioprine/MTX, hepatotoxicity from MTX, nephrotoxicity from calcineurin inhibitors)
Bone density (DEXA)	Baseline + every 1–2 years	Steroid-induced osteoporosis risk
Glucose/HbA1c	Regular	Steroid-induced diabetes
Ophthalmology	Annual (if on HCQ > 5 years)	HCQ retinal toxicity screening
Malignancy screen	Annually for ≥ 3 years	Cancer can appear before, with, or after myositis onset

Long-term immunosuppression and glucocorticoids carry substantial morbidity. Proactive prevention is essential:

Complication	Prevention
Osteoporosis	Calcium + vitamin D supplementation for all patients on prednisolone ≥ 7.5 mg/day > 3 months. Bisphosphonates (alendronate) if DEXA T-score ≤ −1.5 or high fracture risk. DEXA monitoring ^[14]
Steroid-induced diabetes	Regular glucose monitoring; lifestyle advice; start metformin or insulin if needed
Opportunistic infections	Pneumocystis jirovecii pneumonia (PJP) prophylaxis with co-trimoxazole if on high-dose steroids + another immunosuppressant. HBV screening (mandatory in Hong Kong) — start entecavir or tenofovir prophylaxis if HBsAg+ve or anti-HBc+ve before rituximab/cyclophosphamide. TB screening (IGRA + CXR). Vaccination: influenza and pneumococcal ^[16]
GI protection	PPI (e.g. omeprazole) if on high-dose steroids ± NSAIDs
Cardiovascular risk	Steroids increase CV risk → manage BP, lipids, glucose. Steroid → increased CV risk ^[14]
Infertility	Cyclophosphamide → gonadal toxicity. Offer sperm banking/oocyte cryopreservation before starting

HBV Screening Before Immunosuppression — Critical in Hong Kong

Hong Kong has a high prevalence of chronic hepatitis B. Before starting any potent immunosuppression (rituximab, cyclophosphamide, high-dose steroids), always check HBsAg, anti-HBs, anti-HBc. If HBsAg-positive or even isolated anti-HBc-positive, start antiviral prophylaxis (entecavir or tenofovir) to prevent potentially fatal HBV reactivation. Just give them routine HBV DNA monitoring ^[1].

Prognosis: variable depending on type of myositis, severity, delay in diagnosis and autoantibody ^[2] Response to steroid: in general, overlap myositis > DM > PM ^[2]

Factor	Better Prognosis	Worse Prognosis
IIM subtype	Overlap myositis, anti-Mi-2 DM	Anti-SRP AINM, anti-MDA5 CADM
Antibody	Anti-Mi-2, anti-PM/Scl	Anti-MDA5 (rapidly progressive ILD), anti-SRP (refractory), anti-TIF1γ (malignancy)
Organ involvement	Skin-predominant	ILD (especially rapidly progressive), cardiac involvement, severe dysphagia
Response to treatment	Early response to steroids	Delayed diagnosis, refractory to multiple agents
Malignancy	No malignancy found	Cancer-associated myositis

Line	Agent	Indication	Route
1st line	Oral prednisolone 1 mg/kg/day	All overlap myositis	PO
1st line (concurrent)	Azathioprine / Methotrexate / MMF	Steroid-sparing	PO
Severe acute	IV methylprednisolone 500–1000 mg/day × 3–5 days	Fulminant disease, rapidly progressive ILD, respiratory failure	IV
Refractory	IVIG 2 g/kg over 2–5 days	Refractory myositis, severe DM skin	IV
Refractory	Rituximab 1000 mg × 2	Refractory to conventional immunosuppression	IV
Severe ILD	Cyclophosphamide	Rapidly progressive ILD, lupus nephritis	IV pulse
Anti-MDA5 ILD	Tacrolimus + cyclophosphamide + steroids	Triple therapy for rapidly progressive ILD	PO + IV
Progressive fibrotic ILD	Nintedanib	Slows FVC decline despite immunosuppression	PO
Skin	Hydroxychloroquine	DM skin manifestations	PO
Raynaud's	CCB (nifedipine), PDE5i (sildenafil)	Digital vasospasm	PO
Arthritis	NSAIDs, HCQ, MTX	Joint involvement	PO

High Yield Summary — Management of Overlap Myositis

First-line: Oral prednisolone 1 mg/kg/day + concurrent steroid-sparing agent (azathioprine, MTX, or MMF). Taper steroids over months.
Severe/refractory: IV methylprednisolone pulse, IVIG, rituximab. Cyclophosphamide for ILD or organ-threatening overlap disease.
Overlap myositis responds better to steroids than pure DM or PM ^[2] — generally a favourable prognosis.
ILD management is critical: steroids + immunosuppressants; nintedanib for progressive fibrotic phenotype; triple therapy (tacrolimus + cyclophosphamide + steroids) for anti-MDA5 rapidly progressive ILD.
Before azathioprine: check TPMT, NUDT15, and xanthine oxidase inhibitor use ^[18].
Before rituximab/cyclophosphamide: screen for HBV (mandatory in Hong Kong) and TB.
Skin: HCQ + sun protection + topical steroids. Raynaud's: CCB, PDE5i. Dysphagia: speech therapy ± PEG.
Malignancy: treat the cancer — myositis may improve.
Monitor: CK, muscle strength, PFT, CBC/LFT/RFT (drug toxicity), DEXA (osteoporosis), glucose, annual malignancy screen for ≥ 3 years.

Active Recall - Management of Overlap Myositis

References

^[1] Senior notes: Block A - Syncope and irregular heartbeat (p30) — HBV DNA monitoring, overlap vs MCTD ^[2] Senior notes: Ryan Ho Rheumatology (p87, p92) — Management of myositis (steroids, steroid-sparing agents, IVIG, anti-CD20, cyclophosphamide, organ-specific), prognosis, MCTD management ^[3] Senior notes: Ryan Ho Neurology (p194–195) — Inflammatory myopathies management (steroids + immunosuppressants, plasmapheresis, calcineurin inhibitors) ^[11] Senior notes: Maksim Medicine Notes (p320–321) — Non-pharmacological management, pharmacological management (prednisolone dosing, steroid-sparing agents, HCQ, IVIG), malignancy investigations ^[14] Senior notes: Block A - Rheumatology Interactive Tutorial (p2–3) — Steroid side effects (CV risk, osteoporosis, DM), bisphosphonates, steroid taper approach ^[16] Senior notes: Ryan Ho Respiratory (p121–122) — ILD general management (O2, vaccination, lung transplant, antifibrotics), monitoring (PFT follow-up) ^[17] Lecture slides: Neurology - Two cases of lower limb weakness (p41) — DM management (oral prednisolone, steroid-sparing agents azathioprine/MMF, IV methylprednisolone, IVIG, rituximab) ^[18] Senior notes: Block A - Chronic diarrhoea (p45) — Azathioprine pharmacogenomics (TPMT, NUDT15, xanthine oxidase inhibitors)

Complications of Overlap Myositis

Complications in overlap myositis arise from three sources: the disease itself (both the myositis and the overlapping CTD), the consequences of chronic immunosuppressive therapy, and associated malignancy. Understanding these from first principles means tracing each complication back to the pathological process that generates it.

1. Complications of the Myositis Component

1.1 Pulmonary Complications — The Leading Cause of Death

Potential association between cancer and dermatomyositis and the rationale of cancer screening — and equally importantly, investigations of interstitial lung disease ^[15]

Aspect	Detail	Pathophysiological Basis
Prevalence	ILD occurs in ≥ 10% of IIM patients ^[2]; higher in antisynthetase syndrome (up to 60–80%) and anti-MDA5 (virtually universal)	The same autoimmune process attacking muscle also targets the lung interstitium — autoantibodies (particularly antisynthetase antibodies) recognise aminoacyl-tRNA synthetases expressed in both muscle and lung tissue
Pattern	Most commonly NSIP (non-specific interstitial pneumonia) — bibasal GGO sparing subpleural region, reticular changes, traction bronchiectasis, honeycombing RARE ^[16]	NSIP represents a cellular/fibrotic inflammatory process in the alveolar interstitium, driven by lymphocytic infiltration and fibroblast activation
Anti-MDA5 rapidly progressive ILD	CADM with rapidly progressive ILD, skin rash, poor prognosis ^[11] — mortality > 50% at 6 months despite treatment	Anti-MDA5 (melanoma differentiation-associated gene 5) targets an intracellular RNA helicase involved in innate antiviral defence. The antibody drives fulminant alveolar damage with diffuse alveolar haemorrhage pattern
Anti-Jo-1 ILD	Subacute onset; anti-Jo1 antibody is associated with ILD ^[15]; usually NSIP or organising pneumonia pattern	Anti-Jo-1 targets histidyl-tRNA synthetase — an enzyme present in both muscle and lung epithelium. Cross-reactive immune attack damages both tissues
Monitoring	Pulmonary function test shows a reduced forced vital capacity of 70% predicted and diffusion capacity of the lungs for carbon monoxide of 64% predicted ^[15]	Serial PFTs (FVC, DLCO) track progression; declining values despite therapy signal need for treatment escalation

GC High Yield — ILD Is the Most Important Complication

The GC Rheumatology Interactive Tutorial (Case 2) specifically asks: "What are the potential complications?" in the context of dermatomyositis with ILD ^[15]. ILD is the single most important complication to discuss in exams — it determines prognosis and drives management decisions. Always mention ILD first when listing complications of overlap myositis.

Progression of ILD → Pulmonary Hypertension → Right Heart Failure:

Chronic ILD → destruction of pulmonary capillary bed + hypoxic vasoconstriction → ↑pulmonary vascular resistance → pulmonary arterial hypertension (PAH)
PAH → right ventricular afterload ↑ → RV dilatation → right heart failure (cor pulmonale)
This is especially relevant in SSc-overlap myositis where PAH can also be a primary vascular complication independent of ILD

MOST common fatal complications: Aspiration pneumonia due to dysphagia ^[5]

Mechanism	Clinical Scenario
Pharyngeal and oesophageal striated muscle weakness → inability to protect the airway during swallowing → aspiration of food/secretions into the tracheobronchial tree → chemical and bacterial pneumonia	A patient with overlap myositis develops worsening dysphagia and choking episodes. She was admitted due to increasing shortness of breath and new onset difficulty in swallowing food with 2 episodes of choking in the past week ^[14]. Each choking episode risks aspiration

Why is this so dangerous? Because these patients are already immunosuppressed by their treatment → impaired ability to clear the aspirated material → rapid progression to severe pneumonia, sepsis, and death.

Myocarditis: leads to conduction abnormalities and fatal arrhythmia ^[5]

Complication	Mechanism	Clinical Features
Myocarditis	The same autoimmune inflammatory process that attacks skeletal muscle can target cardiac myocytes → lymphocytic infiltration of myocardium → myocyte necrosis	Chest pain, dyspnoea, tachycardia, heart failure (↓EF on echo), elevated troponin. May be subclinical — picked up only on ECG (conduction defects) or echo
Conduction abnormalities	Inflammation of the cardiac conduction system (AV node, bundle of His, Purkinje fibres) → fibrosis and scarring	AV blocks, bundle branch blocks, sinus node dysfunction. Risk of fatal arrhythmia ^[5]
Heart failure	Progressive myocarditis → dilated cardiomyopathy → ↓LVEF → congestive heart failure	Volume overload symptoms (peripheral oedema, pulmonary oedema, raised JVP)
Pericarditis / pericardial effusion	Serosal inflammation (especially in SLE overlap) → pericardial fluid accumulation	Pleuritic chest pain, friction rub. Usually mild but can occasionally cause tamponade

Anti-PM/Scl: identify a small, distinct subgroup of myopathies with a protracted disease course often complicated by pulmonary interstitial fibrosis and/or cardiac involvement ^[13]

Complication	Mechanism	Consequence
Dysphagia	Striated muscle of the upper oesophagus and pharynx is affected by myositis → impaired peristalsis and swallowing	Malnutrition, dehydration, weight loss
Aspiration	As above — pharyngeal weakness → aspiration of oral contents	Aspiration pneumonia (see above)
Nasal regurgitation	Palatal muscle weakness → failure of the soft palate to close off the nasopharynx during swallowing	Food/liquid comes out through the nose — distressing symptom
GORD (in SSc overlap)	Lower oesophageal sphincter smooth muscle replaced by fibrosis → incompetent LOS → acid reflux	Barrett's oesophagus, oesophageal stricture
GI dysmotility (in SSc overlap)	Smooth muscle fibrosis throughout the GI tract → pseudo-obstruction, bacterial overgrowth, malabsorption	Bloating, constipation, diarrhoea, malnutrition

Bulbar muscle involvement has poor prognosis ^[20]

Complication	Mechanism
Muscle wasting and contractures	Chronic uncontrolled inflammation → irreversible fibrosis replacing muscle tissue → fixed contractures. Muscle contractures (tip-toe gait) — childhood form ^[19]
Calcinosis cutis	Dystrophic calcification — calcium and phosphate precipitate in chronically damaged tissue (muscle, subcutaneous tissue). Calcinosis: common in juvenile DM but less so in adult DM ^[2]. Can cause skin ulceration and secondary infection
Functional disability	Progressive proximal weakness → inability to perform ADLs → wheelchair dependence if untreated

Complication	Mechanism	Context
Myoglobinuric AKI	Severe muscle necrosis → massive myoglobin release → myoglobin precipitates in renal tubules at acidic pH → tubular obstruction and direct tubular toxicity → acute kidney injury	Occurs in severe acute myositis with CK > 10,000 IU/L. Dark brown "tea-coloured" urine, dipstick positive for blood but no RBCs on microscopy (myoglobin cross-reacts with the haem peroxidase test)
Lupus nephritis (SLE overlap)	Anti-dsDNA immune complex deposition in glomeruli → proliferative or membranous glomerulonephritis	Only in overlap with SLE. Presents with proteinuria, haematuria, rising creatinine. Renal biopsy (ISN/RPS classification) guides treatment
Scleroderma renal crisis (SSc overlap)	Sudden malignant hypertension with acute oliguric renal failure due to intimal proliferation and fibrinoid necrosis of renal arterioles	Rare but life-threatening. Treated with ACE inhibitors (NOT ARBs). High-dose steroids may precipitate SRC in SSc patients — a critical clinical consideration

Steroid-Induced Scleroderma Renal Crisis

In SSc-overlap myositis, high-dose glucocorticoids (prednisolone > 15 mg/day) can precipitate scleroderma renal crisis. This is one of the most feared iatrogenic complications. If the overlap partner is SSc, try to keep steroid doses as low as possible and use steroid-sparing agents aggressively. Always have ACE inhibitor on standby.

The specific complications depend on which CTD is overlapping. The key principle: overlap myositis inherits ALL the complications of BOTH component diseases.

Overlap Partner	Key Complications Inherited
SLE	Lupus nephritis (leading cause of morbidity), cytopenias (autoimmune haemolytic anaemia, thrombocytopenia), serositis (pleurisy, pericarditis), neuropsychiatric lupus, antiphospholipid syndrome (thrombosis, recurrent miscarriage), accelerated atherosclerosis
SSc	ILD (NSIP or UIP), PAH, scleroderma renal crisis, GI dysmotility, digital ulcers, pulmonary hypertension
RA	Erosive joint destruction, atlanto-axial subluxation, rheumatoid nodules, rheumatoid lung (ILD, bronchiectasis, rheumatoid nodules in lung)
Sjögren syndrome	Keratoconjunctivitis sicca → corneal ulceration, dental caries, parotitis, lymphoma (marginal zone B-cell lymphoma — 5–10% lifetime risk)
MCTD	Pulmonary hypertension (major cause of death in MCTD) ^[2]; ILD; oesophageal dysmotility

Adult form associated with malignancy: 5× risk in dermatomyositis, 2× risk in polymyositis ^[3] Anti-TIF1γ dermatomyositis → high association with malignancy. NXP2 also high association with malignancy ^[4] Dermatomyositis associated with ovarian cancer ^[4]

Aspect	Detail
Risk	DM confers ~5× increased risk; PM confers ~2× risk. The risk in overlap myositis with DM features is similarly elevated
Temporal relationship	Malignancy can be diagnosed before, with, or after onset of myositis ^[3] — most commonly within 1–3 years
Common cancers	NPC (this locality — Hong Kong), adenocarcinomas of bronchus, breast, stomach, ovary, cervix, prostate ^[2]^[3]
High-risk antibodies	Anti-TIF1γ: DM, strongly associated with malignancy (50%) ^[11]; Anti-NXP2: severe weakness and rash, calcinosis, malignancy risk ^[11]
Clinical implication	Must perform thorough malignancy screen at diagnosis and annually for at least 3–5 years: Refer ENT (NPC), Gynae (CA cervix), GI (upper and lower endoscopy) ^[11]; CT TAP ± PET-CT

Long-term immunosuppression and glucocorticoids generate a separate layer of morbidity:

Complication	Mechanism	Prevention/Management
Osteoporosis and fractures	Steroids ↓osteoblast activity + ↑osteoclast activity → ↓bone formation + ↑bone resorption. Also ↓intestinal calcium absorption and ↑renal calcium excretion	Bisphosphonates, or more potent ones ^[14]; calcium + vitamin D supplementation; DEXA monitoring
Steroid-induced diabetes	Steroids ↑hepatic gluconeogenesis + ↓peripheral insulin sensitivity → hyperglycaemia	DM control — discussed for possible need for insulin therapy ^[14]; regular glucose monitoring
Cushingoid features	Exogenous hypercortisolism → central obesity, moon face, buffalo hump, striae, thin skin, easy bruising	Dose-dependent; minimised by steroid taper
Avascular necrosis (AVN)	Steroids → fat embolism of intraosseous vessels OR lipocyte hypertrophy → ↑intraosseous pressure → ischaemic necrosis of bone (especially femoral head)	MRI if hip pain develops; may need joint replacement
Steroid myopathy	Type IIb fibre atrophy from protein catabolism (NO fibre necrosis → CK is normal)	A critical diagnostic dilemma — worsening weakness with normal CK on steroids = steroid myopathy, not disease flare
Immunosuppression → infections	Broad suppression of innate and adaptive immunity → susceptibility to bacterial, viral, fungal, and opportunistic infections	Pneumocystis prophylaxis (co-trimoxazole), vaccination (influenza and pneumococcal) ^[16], HBV prophylaxis
Cardiovascular risk	Steroid → increased CV risk ^[14] — steroids promote dyslipidaemia, hypertension, insulin resistance, central obesity	CV risk factor management (BP, lipids, glucose, lifestyle)
Cataracts and glaucoma	Posterior subcapsular cataract from altered lens protein metabolism; open-angle glaucoma from ↑aqueous humor outflow resistance	Annual ophthalmology screening
Adrenal suppression	Chronic exogenous steroids → HPA axis suppression → adrenal atrophy. Abrupt withdrawal → adrenal crisis (hypotension, shock)	Never stop steroids abruptly; always taper gradually; educate patient on sick-day rules (double dose during illness/surgery)

Agent	Key Complications
Azathioprine	Bone marrow suppression, allergy, hepatotoxicity, pancreatitis ^[18]. Risk amplified by TPMT/NUDT15 deficiency or concurrent xanthine oxidase inhibitors
Methotrexate	Hepatotoxicity (fibrosis/cirrhosis with chronic use), myelosuppression, MTX pneumonitis (hypersensitivity reaction — important to distinguish from myositis-ILD), teratogenicity, oral ulcers
Cyclophosphamide	Haemorrhagic cystitis (prevented by MESNA and adequate hydration), gonadal toxicity, secondary malignancy (bladder cancer, haematological), myelosuppression
Rituximab	HBV reactivation (mandatory screening in HK ^[1]), progressive multifocal leukoencephalopathy (PML — JC virus), hypogammaglobulinaemia with recurrent infections, infusion reactions
Calcineurin inhibitors	Nephrotoxicity, hypertension, neurotoxicity (tremor, seizures), hyperglycaemia, gingival hypertrophy (ciclosporin), hyperkalaemia
MMF	GI toxicity (nausea, diarrhoea), myelosuppression, teratogenicity
HCQ	Retinal toxicity (bull's eye maculopathy) — annual ophthalmology review after 5 years of use

The combination of high-dose steroids + another immunosuppressant creates a state of profound immunosuppression. Key opportunistic infections to watch for:

Infection	Pathogen	Risk Factor	Prevention
Pneumocystis pneumonia (PJP)	Pneumocystis jirovecii	High-dose steroids + immunosuppressant	Co-trimoxazole prophylaxis (960 mg 3×/week)
HBV reactivation	Hepatitis B virus	Rituximab, cyclophosphamide, high-dose steroids in HBsAg+ve or anti-HBc+ve patient	Antiviral prophylaxis (entecavir/tenofovir); routine HBV DNA monitoring ^[1]
TB reactivation	Mycobacterium tuberculosis	Any potent immunosuppression	IGRA + CXR screening before treatment; isoniazid prophylaxis if latent TB
Herpes zoster	Varicella-zoster virus reactivation	Calcineurin inhibitors, JAK inhibitors, steroids	Recombinant zoster vaccine (Shingrix) if eligible
CMV reactivation	Cytomegalovirus	Intense immunosuppression	Monitor CMV PCR if febrile on heavy immunosuppression

Organ System	Complications	Antibody Association
Lung	ILD (NSIP, OP, DAD), aspiration pneumonia, respiratory failure, PAH	Anti-Jo-1, anti-MDA5, anti-PM/Scl
Heart	Myocarditis, arrhythmia, heart failure, pericarditis	Anti-PM/Scl, anti-SRP
Oesophagus/GI	Dysphagia, aspiration, nasal regurgitation, GORD, GI dysmotility	(SSc overlap)
Musculoskeletal	Contractures, calcinosis, functional disability	Anti-NXP2 (calcinosis)
Kidney	Myoglobinuric AKI, lupus nephritis, scleroderma renal crisis	Anti-dsDNA (LN), anti-RNA pol III (SRC)
Malignancy	NPC, adenocarcinomas (lung, breast, ovary, stomach, cervix)	Anti-TIF1γ, anti-NXP2
Iatrogenic	Osteoporosis, DM, infections, AVN, steroid myopathy, myelosuppression, hepatotoxicity, infertility	(Treatment-related)

High Yield Summary — Complications of Overlap Myositis

MOST common fatal complications: aspiration pneumonia, ILD, and myocarditis ^[5]. These three account for the majority of myositis-related deaths.
ILD is the single most important complication — drives prognosis. Anti-Jo-1 → subacute NSIP; anti-MDA5 → rapidly progressive ILD with very high mortality.
Bulbar muscle involvement has poor prognosis ^[20] — dysphagia leads to aspiration pneumonia and malnutrition.
Malignancy: 5× risk in DM, 2× risk in PM. NPC is the key cancer in Hong Kong ^[3]. Anti-TIF1γ and anti-NXP2 carry highest malignancy risk. Screen annually for ≥ 3 years.
Cardiac: myocarditis → conduction abnormalities → fatal arrhythmia. Anti-PM/Scl identifies a subgroup with cardiac involvement.
Renal: myoglobinuric AKI (severe myositis), lupus nephritis (SLE overlap), scleroderma renal crisis (SSc overlap — beware steroids can precipitate this).
Treatment complications are a major source of morbidity: steroid-induced osteoporosis, diabetes, AVN, steroid myopathy; azathioprine myelosuppression; MTX pneumonitis; cyclophosphamide haemorrhagic cystitis; rituximab HBV reactivation.
Always distinguish steroid myopathy from disease flare: flare = rising CK; steroid myopathy = normal CK.

Active Recall - Complications of Overlap Myositis

References

^[1] Senior notes: Block A - Syncope and irregular heartbeat (p30) — HBV DNA monitoring ^[2] Senior notes: Ryan Ho Rheumatology (p87, p90–92) — ILD prevalence, cutaneous features, malignancy risk, MCTD complications (PAH), prognosis ^[3] Senior notes: Ryan Ho Neurology (p194–195) — Malignancy types and temporal relationship, inflammatory myopathies classification ^[4] Senior notes: Block A - Dermatology PBL 2 (p6–7) — Anti-TIF1γ, anti-NXP2 malignancy association, dermatomyositis and ovarian cancer ^[5] Senior notes: MBBS Final MB Medicine - Felix PY Lai (p1762, p1764) — Most common fatal complications (aspiration pneumonia, ILD, myocarditis with conduction abnormalities and fatal arrhythmia) ^[11] Senior notes: Maksim Medicine Notes (p320–321) — Anti-MDA5 rapidly progressive ILD, anti-TIF1γ malignancy, anti-NXP2 calcinosis, malignancy screening ^[13] Senior notes: MBBS Final MB Pediatrics - Felix PY Lai (p709) — Anti-PM/Scl: protracted course with pulmonary fibrosis and cardiac involvement ^[14] Senior notes: Block A - Rheumatology Interactive Tutorial (p2–3) — Steroid complications (osteoporosis, DM, CV risk), GC Rheum Case 2 clinical scenario (dysphagia, choking episodes) ^[15] Lecture slides: GC Interactive tutorial Rheum case 2 student copy (p1, p6) — Learning objectives (ILD investigation, cancer screening), further investigation findings ^[16] Senior notes: Ryan Ho Respiratory (p121–124) — ILD management and monitoring, NSIP, vaccination, long-term O₂, lung transplant ^[18] Senior notes: Block A - Chronic diarrhoea (p45) — Azathioprine side effects (bone marrow suppression, allergy, hepatotoxicity, pancreatitis) ^[19] Senior notes: Adrian Lui Pediatrics Notes (p145–146) — PM/DM clinical features (respiratory failure, muscle contractures, calcinosis), mortality ^[20] Lecture slides: GC 053. Fingers turn white and blue (p44) — Bulbar muscle involvement has poor prognosis

High Yield Summary

Overlap myositis = inflammatory myopathy (PM or DM) coexisting with another well-defined CTD (most commonly SSc, SLE, MCTD, less commonly RA, Sjögren)
Distinguished from MCTD: overlap has two fully expressed diseases; MCTD has mild/incomplete forms with anti-U1 RNP
Pathophysiology: PM-type (CD8+ T-cell endomysial infiltration) or DM-type (B-cell/complement perimysial microangiopathy), PLUS the pathology of the overlapping CTD
Key antibodies indicating overlap tendency: anti-PM-Scl (SSc overlap), anti-Ku, anti-U1 RNP (MCTD)
Antisynthetase syndrome (anti-Jo-1): myositis + ILD + mechanic's hands + arthritis + Raynaud's + fever — often classified under overlap
Clinical features: proximal symmetric weakness + skin signs (if DM) + features of overlapping CTD + ILD + constitutional symptoms
Malignancy screening is essential, especially in HK: screen for NPC, adenocarcinomas; anti-TIF1γ and anti-NXP2 carry highest risk
Gottron's papules are pathognomonic for DM; DM facial erythema involves nasolabial folds (unlike SLE which spares them)
Prognosis of overlap myositis is generally better than pure PM, but ILD (especially anti-MDA5 associated) is the major driver of mortality

High Yield Summary — Differential Diagnosis

Closest differentials: other IIM subtypes (pure DM, pure PM, IBM, AINM, antisynthetase syndrome). The key to overlap myositis is the presence of another well-defined CTD alongside the myositis.
Hypothyroid myopathy is the most important endocrine mimic — always check TFT ^[9].
Steroid myopathy is the most important iatrogenic mimic in a patient already on treatment — CK is normal (no fibre necrosis).
MG is distinguished by fatigability, normal CK, and anti-AChR antibodies ^[9].
IBM is distinguished by insidious onset, distal > proximal pattern, older males, and poor response to treatment ^[9].
Drug-induced myopathy (statins, glucocorticoids, colchicine) must always be considered — check the drug chart ^[7].
Always screen for malignancy in any new inflammatory myositis, especially DM in elderly: NPC is the key malignancy in Hong Kong ^[2]^[3].
MCTD vs overlap: MCTD has mild/incomplete forms of each disease with anti-U1 RNP; overlap has fully expressed discrete diseases ^[1].

High Yield Summary — Diagnostic Criteria, Algorithm and Investigations

Bohan-Peter criteria (1975): PM = all 4 of proximal weakness + elevated CK + myopathic EMG + positive biopsy. DM = typical rash + any 3 of the 4. Still the most examined criteria.
2017 EULAR/ACR criteria: Probability-based scoring; includes anti-Jo-1 (heavily weighted at 3.9 points without biopsy).
Troyanov classification (GC 056): Overlap myositis = myositis + overlap features (other than rash) and/or overlap autoAb (anti-U1RNP, anti-PM/Scl, anti-Ku, anti-U3RNP). Antisynthetase syndrome is included.
"2 out of 3" practical rule: elevated CK + myopathic EMG + positive muscle biopsy — need 2 of 3 to confirm myositis.
Overlap myositis has heterogeneous or non-specific muscle histology — autoantibodies are especially important for classification.
Key investigations: CK (most sensitive muscle marker), EMG (myopathic pattern), muscle biopsy (definitive), autoantibodies (classification + prognosis), HRCT + PFT (ILD), malignancy screening (mandatory in DM, especially NPC in HK).
Always check TFT to exclude hypothyroid myopathy and review drug chart for statin/steroid myopathy.
Always screen for HBV before immunosuppression in Hong Kong.

High Yield Summary — Management of Overlap Myositis

First-line: Oral prednisolone 1 mg/kg/day + concurrent steroid-sparing agent (azathioprine, MTX, or MMF). Taper steroids over months.
Severe/refractory: IV methylprednisolone pulse, IVIG, rituximab. Cyclophosphamide for ILD or organ-threatening overlap disease.
Overlap myositis responds better to steroids than pure DM or PM ^[2] — generally a favourable prognosis.
ILD management is critical: steroids + immunosuppressants; nintedanib for progressive fibrotic phenotype; triple therapy (tacrolimus + cyclophosphamide + steroids) for anti-MDA5 rapidly progressive ILD.
Before azathioprine: check TPMT, NUDT15, and xanthine oxidase inhibitor use ^[18].
Before rituximab/cyclophosphamide: screen for HBV (mandatory in Hong Kong) and TB.
Skin: HCQ + sun protection + topical steroids. Raynaud's: CCB, PDE5i. Dysphagia: speech therapy ± PEG.
Malignancy: treat the cancer — myositis may improve.
Monitor: CK, muscle strength, PFT, CBC/LFT/RFT (drug toxicity), DEXA (osteoporosis), glucose, annual malignancy screen for ≥ 3 years.

High Yield Summary — Complications of Overlap Myositis

MOST common fatal complications: aspiration pneumonia, ILD, and myocarditis ^[5]. These three account for the majority of myositis-related deaths.
ILD is the single most important complication — drives prognosis. Anti-Jo-1 → subacute NSIP; anti-MDA5 → rapidly progressive ILD with very high mortality.
Bulbar muscle involvement has poor prognosis ^[20] — dysphagia leads to aspiration pneumonia and malnutrition.
Malignancy: 5× risk in DM, 2× risk in PM. NPC is the key cancer in Hong Kong ^[3]. Anti-TIF1γ and anti-NXP2 carry highest malignancy risk. Screen annually for ≥ 3 years.
Cardiac: myocarditis → conduction abnormalities → fatal arrhythmia. Anti-PM/Scl identifies a subgroup with cardiac involvement.
Renal: myoglobinuric AKI (severe myositis), lupus nephritis (SLE overlap), scleroderma renal crisis (SSc overlap — beware steroids can precipitate this).
Treatment complications are a major source of morbidity: steroid-induced osteoporosis, diabetes, AVN, steroid myopathy; azathioprine myelosuppression; MTX pneumonitis; cyclophosphamide haemorrhagic cystitis; rituximab HBV reactivation.
Always distinguish steroid myopathy from disease flare: flare = rising CK; steroid myopathy = normal CK.

Overlap Myositis

1. Definition

2. Epidemiology

2.1 Incidence and Prevalence

2.2 Demographics

2.3 Risk Factors

2.4 Hong Kong / Asia-Pacific Relevance

3. Anatomy and Function — What Is Being Damaged?

3.1 Skeletal Muscle Architecture (relevant to understanding weakness)

3.2 Other Organ Systems Involved

4. Aetiology and Pathophysiology

4.1 Aetiology

4.2 Pathophysiology — Muscle Damage

4.2.1 Polymyositis-type Mechanism

4.2.2 Dermatomyositis-type Mechanism

4.2.3 Autoimmune Necrotising Myopathy (AINM)

4.2.4 Why "Overlap"?

4.3 Pathophysiology Summary Flowchart

5. Classification

5.1 Classification of Idiopathic Inflammatory Myopathies (IIMs)

5.2 Classification by Overlapping CTD

5.3 Classification by Myositis-Specific Antibody (MSA) — Clinico-Serological Subsets

6. Clinical Features

6.1 Symptoms

6.1.1 Muscle Symptoms — The Myositis Component

6.1.2 Cutaneous Symptoms (if DM component present)

6.1.3 Symptoms from the Overlapping CTD

6.1.4 Pulmonary Symptoms

6.1.5 Constitutional Symptoms

6.2 Signs

6.2.1 Musculoskeletal Signs

6.2.2 Cutaneous Signs (DM component)

6.2.3 Signs of the Overlapping CTD

6.2.4 Respiratory Signs

6.2.5 Cardiac Signs (if present)

6.2.6 Nailfold Capillaroscopy Findings

7. Key Distinguishing Features from Other IIM Subtypes

8. Antisynthetase Syndrome — A Special Overlap Phenotype

9. Malignancy Association

Active Recall - Overlap Myositis

References

Approach — Thinking From First Principles

Systematic Differential Diagnosis Framework

Detailed Differential Diagnosis Table

A. Other Idiopathic Inflammatory Myopathies (IIMs)

B. Other Connective Tissue Diseases Presenting with Myopathy-like Features

C. Endocrine and Metabolic Myopathies

D. Drug-Induced Myopathy

E. Neuromuscular Junction Disorders

F. Muscular Dystrophies

G. Infectious Myositis

H. Other

Diagnostic Approach Flowchart — Differential Diagnosis of Proximal Weakness

Summary Table: Key Distinguishing Features

Active Recall - Differential Diagnosis of Overlap Myositis

1. Diagnostic Criteria

1.1 Criteria for the Myositis Component

A. Classic Bohan and Peter Criteria (1975) — Still Widely Taught and Examined

B. 2017 EULAR/ACR Classification Criteria for IIM — The Current Standard

C. Troyanov Classification for Overlap Myositis Specifically

D. Defining the Myositis Component — Practical Clinical Rule

1.2 Criteria for the Overlapping CTD Component

2. Diagnostic Algorithm

3. Investigation Modalities — Detailed Guide

3.1 Blood Tests

A. Muscle Enzymes

B. Inflammatory Markers

C. General Screening Bloods

D. Cardiac Enzymes

3.2 Autoantibodies — The Serological Key to Subtyping

A. Myositis-Specific Antibodies (MSAs)

B. Myositis-Associated Antibodies (MAAs) — The Overlap Clue

C. CTD-Specific Antibodies (to confirm the overlapping disease)

D. ANA — The Screening Test

3.3 Electromyography (EMG)

3.4 Muscle Biopsy — The Definitive Investigation

When to Biopsy

Biopsy Technique

Histopathological Findings

3.5 MRI of Skeletal Muscles