Decision support only — not a substitute for neurology/rheumatology, the ACR/EULAR and ENMC criteria, or specialist genetic and neuromuscular services. The work-up earns its keep by separating what you can reverse and what can kill from what is neither. History and the pattern of weakness drive the investigations; the myositis-antibody revolution has reorganised inflammatory myopathy around serology; and genetic testing (panels, exome, genome) has taken over much of hereditary diagnosis, with biopsy reserved for acquired disease or when genetics come back negative. Verify all doses and local access.
1 Two questions that run in parallel
Catch the treatable reversible
- ImmuneDermatomyositis, antisynthetase, necrotizing myopathy — steroids, IVIG, rituximab (§5).
- PompeLate-onset, limb-girdle + early respiratory weakness — screen with dried-blood-spot GAA; enzyme replacement works (§8).
- ToxicStatins, colchicine, steroids, alcohol, checkpoint inhibitors — stop the drug (§7).
- EndocrineHypothyroid, Cushing's, hyperparathyroid, vitamin D — treat the gland (§7).
Catch the dangerous can kill
- RhabdoAKI, hyperkalaemia, compartment syndrome — CK often >5000 (§6).
- CardiacConduction block, arrhythmia, cardiomyopathy — myotonic dystrophy, LMNA, dystrophinopathy → ECG + echo + rhythm monitoring (§8).
- RespiratoryDiaphragm weakness → hypoventilation — Pompe, anti-MDA5/antisynthetase ILD → FVC sitting & supine.
- AirwayDysphagia → aspiration (IBM, DM); MDA5 rapidly progressive ILD is a killer (§4–5).
2 Approach — pattern of weakness, then investigate
The distribution and tempo of weakness narrow the field before any test. Proximal-symmetric is the common inflammatory/metabolic/endocrine pattern; a few distributions are almost diagnostic on their own.
| Pattern | Points toward |
|---|
| Proximal, symmetric (limb-girdle) | Inflammatory myopathy, necrotizing myopathy, endocrine, toxic, Pompe, limb-girdle dystrophy |
| Asymmetric, finger flexors + quadriceps, falls, dysphagia, age >50 | Inclusion body myositis — the pattern is the diagnosis |
| Facial + scapular winging | Facioscapulohumeral dystrophy (FSHD) |
| Distal + grip myotonia, ptosis, frontal balding | Myotonic dystrophy (DM1) — ask about the heart (§8) |
| Episodic / exertional, cramps, myoglobinuria | Metabolic myopathy (McArdle, CPT2), channelopathy — investigate recurrent rhabdo (§6) |
| Rapidly progressive, very high CK | Immune-mediated necrotizing myopathy, rhabdomyolysis |
Core investigations
- CKDegree helps: very high → necrotizing/rhabdo; normal-mild doesn't exclude (steroid myopathy, IBM, some dystrophies).
- EMG/NCSConfirms myopathic changes ± irritability; separates neurogenic and neuromuscular-junction disease.
- Muscle MRIShows oedema vs fatty replacement and the pattern; targets the biopsy.
Antibodies, biopsy, genes
- AntibodiesMyositis-specific/associated panel — often defines the subtype and its risks (§4).
- BiopsyStill central for acquired disease, and for hereditary disorders when genetic testing is negative.
- GeneticsMulti-gene panels, whole-exome, whole-genome now carry most hereditary diagnosis.
3 Inflammatory myopathies — the modern subtypes
Serology and pathology have replaced the old "polymyositis/dermatomyositis" split. Current classification (ACR/EULAR 2017; ENMC) recognises four core groups plus overlap. Polymyositis is now largely a diagnosis of exclusion — most such cases are actually necrotizing myopathy, antisynthetase syndrome, or overlap.
| Subtype | Clinical | Antibodies | Treatment / notes |
|---|
| Dermatomyositis |
Gottron papules, heliotrope, shawl sign; proximal weakness (or amyopathic); ILD; cancer risk |
Mi-2, TIF1-γ, NXP2, MDA5, SAE |
Steroid + sparing agent + IVIG; screen for malignancy |
| Antisynthetase syndrome |
Myositis + ILD + arthritis + mechanic's hands + fever + Raynaud |
Jo-1, PL-7, PL-12, EJ, OJ |
ILD drives prognosis and treatment; immunosuppress |
| Necrotizing myopathy (IMNM) |
Severe proximal weakness, very high CK, necrosis with little inflammation |
SRP; HMGCR (statin); or seronegative |
Early aggressive immunosuppression + IVIG; often refractory |
| Inclusion body myositis |
>50, insidious, asymmetric finger-flexor + quadriceps, dysphagia |
cN1A (also Sjögren/SLE) |
Does not respond to immunosuppression — supportive; trials ongoing (§5) |
| Overlap myositis |
Myositis with another connective-tissue disease |
PM-Scl, Ku, U1-RNP, Ro52 |
Treat the overlap; Ro52 flags worse ILD |
4 Myositis-specific antibodies — what each one tells you
The reason to send the panel is that each antibody predicts organ involvement, cancer risk, and treatment response. These are the "novel antibodies" that reorganised the field.
| Antibody | Phenotype | What it flags |
|---|
| Anti-MDA5 | DM, often amyopathic; skin ulcers | rapidly progressive ILD, high mortality — treat hard, fast |
| Anti-TIF1-γ | Dermatomyositis | malignancy — screen for cancer |
| Anti-NXP2 | Dermatomyositis | malignancy, calcinosis |
| Anti-Mi-2 | Classic DM rash + myositis | good prognosis, treatment-responsive |
| Anti-Jo-1 & other synthetases | Antisynthetase syndrome | ILD — monitor PFTs / HRCT |
| Anti-SRP | Necrotizing myopathy | severe, very high CK, refractory |
| Anti-HMGCR | Necrotizing myopathy | statin-triggered — but can be statin-naïve; persists after stopping the statin |
| Anti-cN1A | Inclusion body myositis | supports IBM (also seen in Sjögren/SLE) |
| Anti-Ro52 (associated) | Overlap marker | worse ILD, often with synthetase antibodies |
5 Treating inflammatory myopathy
The backbone
- SteroidsHigh-dose glucocorticoids, then taper — first-line for DM, antisynthetase, IMNM.
- SparingAdd early: methotrexate, azathioprine, or mycophenolate.
- CancerScreen for malignancy in DM, especially TIF1-γ / NXP2.
Escalation
- IVIGProven in dermatomyositis ProDERM (now approved for DM); useful in anti-HMGCR IMNM and for dysphagia.
- RituximabRefractory DM, antisynthetase, IMNM.
- MDA5-ILDRapidly progressive ILD → early triple therapy (steroid + calcineurin inhibitor + cyclophosphamide) ± JAK inhibitor ± rituximab. High mortality.
IBM is the exception
- Don'tImmunosuppression doesn't work in IBM — avoid committing patients to long-term steroids.
- DoExercise, falls prevention, and dysphagia management (including cricopharyngeal intervention).
- TrialsSirolimus (phase 3, incl. Australia); ulviprubart (anti-KLRG1) missed its primary endpoint in 2026 but signalled benefit in milder disease; ruxolitinib in trials.
6 Rhabdomyolysis
Recognise
- CK>5× ULN, often >5000–10000; myalgia, weakness, dark urine.
- UrineDipstick positive for blood with few red cells = myoglobinuria.
- CausesTrauma/crush, immobility, exertion/heat, seizures, drugs/toxins (statins, alcohol, stimulants), infection, metabolic.
The complications
- KidneyAKI from myoglobin — the main threat.
- ElectrolytesHyperkalaemia (arrhythmia), hyperphosphataemia, hypocalcaemia; later rebound hypercalcaemia.
- LocalCompartment syndrome; DIC in severe cases.
Manage & think again
- FluidsEarly aggressive IV crystalloid to a urine-output target; monitor K/Ca/PO4 and rhythm.
- UnprovenBicarbonate and mannitol lack clear benefit — fluids are the priority.
- RecurrentRecurrent or exertional rhabdo → investigate a metabolic myopathy or RYR1/genetic cause.
7 Toxic & endocrine myopathy
Drugs — and the statin trichotomy
- StatinsThree different things: (1) common self-limited myalgia that resolves on stopping; (2) rare rhabdomyolysis; (3) anti-HMGCR necrotizing myopathy that progresses after the statin stops and needs immunosuppression. Don't blur them.
- OthersGlucocorticoids (type II atrophy, normal CK), colchicine, alcohol, amiodarone, antimalarials.
- CheckpointICI myositis can overlap with myocarditis + myasthenia — a high-mortality triad. Check troponin/ECG, hold the drug, give steroids urgently.
Endocrine — reversible
- ThyroidHypothyroid (raised CK, proximal weakness, slow-relaxing reflexes) and thyrotoxic myopathy both improve with treatment.
- SteroidCushing's / exogenous steroid — proximal weakness, normal CK.
- OtherHyperparathyroidism, vitamin D deficiency, acromegaly.
8 Genetic myopathies & muscular dystrophies
Genetic testing now leads hereditary diagnosis, with biopsy in reserve. Two themes matter at the bedside: find the treatable one (Pompe), and protect the heart in the ones that cause conduction disease.
Pompe — the treatable one screen
- PictureLate-onset: limb-girdle weakness with early diaphragm/respiratory involvement, raised CK.
- TestDried-blood-spot GAA enzyme, then confirm the GAA gene — easy to miss, easy to screen.
- TreatEnzyme replacement: alglucosidase alfa; avalglucosidase alfa COMET; cipaglucosidase + miglustat PROPEL.
Protect the heart
- MyotonicDM1 (DMPK expansion): multisystem — myotonia, cataracts, endocrine, somnolence; conduction block/arrhythmia/sudden death → annual ECG, low threshold for pacemaker/ICD.
- OthersDystrophinopathy, LMNA/Emery-Dreifuss, sarcoglycanopathy → cardiomyopathy/conduction disease → ECG + echo + rhythm monitoring.
The dystrophies
- DystrophinDuchenne (severe, childhood) & Becker (milder); DMD gene, X-linked; cardiac + respiratory surveillance mandatory.
- OthersLimb-girdle (many genes), FSHD (facioscapular), myotonic.
New therapies — real, but read the fine print
- DuchenneCorticosteroids and vamorolone; exon-skipping antisense (eteplirsen, golodirsen, viltolarsen, casimersen — mutation-specific, modest); ataluren (nonsense mutations); givinostat (HDAC inhibitor, 2024).
- Gene therapyDelandistrogene moxeparvovec (Elevidys) — AAV microdystrophin, accelerated approval 2023, expanded 2024. Approved substantially on microdystrophin expression; clinical-benefit data are mixed (some endpoints missed), it costs ~US$3.2M, and AAV gene therapy carries real safety risk. Promising, not settled.
- IBM/othersNo disease-modifying therapy yet for IBM (§5); enzyme replacement remains the model of a genuinely disease-modifying muscle treatment (Pompe).
Classification & guidelines. ACR/EULAR 2017 classification criteria for adult and juvenile idiopathic inflammatory myopathies; ENMC criteria (IMNM 2018; inclusion body myositis, 272nd ENMC workshop); AAN "Evidence in Focus" on delandistrogene moxeparvovec (2024); eTG; PBS.
NEJM reviews. Dalakas, "Inflammatory Muscle Diseases," NEJM 2015; Mammen, "Statin-Associated Autoimmune Myopathy," NEJM 2016. Background: Nature Reviews Disease Primers — idiopathic inflammatory myopathies (2021).
Trials. ProDERM (IVIG in dermatomyositis, NEJM 2022 — basis for DM approval); RIM (rituximab in myositis); sirolimus in IBM (Lancet Rheumatol 2021; phase 3 ongoing); ulviprubart/ABC008 anti-KLRG1 in IBM (phase 2/3, missed primary endpoint 2026, signal in milder disease); COMET (avalglucosidase alfa) & PROPEL (cipaglucosidase + miglustat) in late-onset Pompe; delandistrogene moxeparvovec (Elevidys) DMD gene therapy (FDA 2023, expanded 2024); givinostat (Duvyzat, 2024).
Caveats. Antibody testing predicts organ risk (ILD, cancer) and treatment response — send the panel. Anti-HMGCR myopathy can occur without statin exposure and persists after stopping. IBM does not respond to immunosuppression. Recurrent/exertional rhabdomyolysis warrants a metabolic-myopathy work-up. DMD gene therapy is approved largely on biomarker data with clinical benefit still being confirmed. Verify all doses and local access. Companion to the neurology set (MND, MS) and to the ILD sheet.