Laboratory investigations - antibodies associated with inflammatory myositis

Antibody families

Antibodies used to define inflammatory neurological and neuromuscular syndromes - where the antibody often names the disease and dictates the treatment
Two mechanistic families
- Cell-surface antigen (NMDAR, LGI1, AQP4, MuSK, AChR, gangliosides) -> directly pathogenic, antibody-depleting therapy works, good response
- Intracellular antigen (Hu, Yo, Ri, Ma2, GAD65, amphiphysin) -> T-cell mediated, antibody is a marker not the cause, poor response, strong cancer association

Autoimmune encephalitis incidence ~1-2/100,000/yr - now comparable to viral encephalitis
Anti-NMDAR is the commonest: young, F>M, median age ~21
GBS ~1-2/100,000/yr; Miller Fisher variant ~5% of GBS in Western countries, up to 20-25% in East Asia

Molecular mimicry - the paradigm for post-infectious neuropathy
- **Campylobacter jejuni lipo-oligosaccharide mimics ganglioside epitopes** -> antibody cross-reacts with peripheral nerve
- GQ1b is enriched in the paranodal myelin of cranial nerves III, IV and VI, and in muscle spindle afferents -> explains ophthalmoplegia and ataxia
Tumour-driven: ectopic neuronal antigen expression by a tumour -> anti-tumour immunity attacks nervous system
- Teratoma in NMDAR encephalitis, SCLC in Hu/CRMP5, gynaecological/breast in Yo
Post-viral: HSV encephalitis triggers NMDAR antibodies in 20-30% -> relapse weeks later with a movement disorder

Antibody	Syndrome	Features
Anti-GQ1b	Miller Fisher syndrome	Ophthalmoplegia + ataxia + areflexia (the triad); positive in >85-90%. Also Bickerstaff brainstem encephalitis and the pharyngeal-cervical-brachial variant
Anti-GM1, anti-GD1a	AMAN (acute motor axonal neuropathy)	Post-Campylobacter, pure motor, axonal on NCS
Anti-GM1 (IgM)	Multifocal motor neuropathy with conduction block	Asymmetric arm weakness without sensory loss; mimics MND but treatable with IVIg
Anti-MAG (IgM)	Distal acquired demyelinating symmetric neuropathy	IgM paraprotein, sensory ataxia, tremor, very prolonged distal latencies
Anti-GD1b / disialosyl	CANOMAD	Chronic ataxic neuropathy, ophthalmoplegia, cold agglutinins

Anti-AChR - myasthenia gravis, 85% of generalised disease, ~50% ocular. Thymoma in 10-15%
Anti-MuSK - 5-8%; bulbar and respiratory predominance, facial wasting, poor response to anticholinesterases, excellent response to rituximab
Anti-LRP4, anti-agrin - seronegative subgroups
Anti-VGCC (P/Q type) - Lambert-Eaton; SCLC in ~50-60%; incremental response post-exercise

Antibody	Syndrome	Tumour
Anti-NMDAR	Psychiatric prodrome -> seizures -> orofacial dyskinesia, autonomic instability, hypoventilation	Ovarian teratoma ~40% in young women
Anti-LGI1	Limbic encephalitis, faciobrachial dystonic seizures, hyponatraemia	Rare
Anti-CASPR2	Morvan syndrome, neuromyotonia, neuropathic pain	Thymoma
Anti-AQP4 (NMO-IgG)	Neuromyelitis optica spectrum disorder - longitudinally extensive myelitis, area postrema syndrome	-
Anti-MOG	MOGAD - ADEM, bilateral optic neuritis	-
Anti-Hu (ANNA-1)	Sensory neuronopathy, encephalomyelitis	SCLC
Anti-Yo (PCA-1)	Cerebellar degeneration	Ovary, breast
Anti-Ma2	Limbic/brainstem encephalitis	Testicular germ cell
Anti-GAD65	Stiff person, cerebellar ataxia, epilepsy	Rare; T1DM overlap

Test paired serum AND CSF - NMDAR is more sensitive in CSF; LGI1 and AQP4 in serum
Cell-based assays outperform ELISA and line blots - insist on CBA for AQP4, MOG, NMDAR
Low-titre MOG and GAD are frequently false positives - interpret only against the phenotype
A negative antibody does not exclude autoimmune encephalitis - treat on clinical, CSF, MRI and EEG criteria
Tumour search: CT chest/abdomen/pelvis, pelvic US or MRI for teratoma, testicular US, FDG-PET if negative and suspicion high

Cell-surface antibody syndromes - treat early and hard
- First line: high-dose methylprednisolone + IVIg or plasma exchange
- Second line if no response in ~2 weeks: rituximab +/- cyclophosphamide - substantially improves outcome and reduces relapse
- Remove the tumour - teratoma resection is therapeutic in NMDAR encephalitis
Intracellular antigen (paraneoplastic) syndromes
- Treat the tumour - the single most effective intervention
- Immunotherapy response is poor; do not delay oncological treatment while trialling it
Miller Fisher / GBS: IVIg 0.4 g/kg/day for 5 days, or plasma exchange - equivalent, not additive
- Corticosteroids are ineffective in GBS
- Monitor FVC (not oximetry), bulbar function, autonomic instability
NMOSD relapse prevention: eculizumab, satralizumab, inebilizumab or rituximab
- *Interferon-beta, natalizumab and fingolimod worsen NMOSD - never treat as MS without an AQP4 result*
Myasthenia: pyridostigmine, prednisolone, steroid-sparing agent, thymectomy if AChR+ with thymoma or generalised disease under 50; rituximab early in MuSK

Campylobacter jejuni, CMV, EBV, Mycoplasma, Zika, HEV - antecedent infection in GBS
HSV encephalitis -> post-infectious NMDAR encephalitis
Immune checkpoint inhibitors - a rapidly growing cause of myasthenia, myositis, encephalitis and neuropathy (myasthenia + myocarditis + myositis overlap carries high mortality)
SCLC, thymoma, ovarian teratoma, breast and gynaecological malignancy
Other autoimmune disease - thyroiditis, T1DM, coeliac

Miller Fisher: excellent prognosis - most recover fully within 3-6 months without treatment; contrast GBS overall, where ~20% remain unable to walk unaided at 6 months
Anti-NMDAR: ~80% good outcome, but recovery takes 12-24 months; relapse 12-25%, lower after rituximab and after teratoma removal
Paraneoplastic syndromes with intracellular antibodies: usually stabilisation at best; deficits are fixed because neuronal loss has occurred
The single strongest predictor of outcome across cell-surface syndromes is time from onset to immunotherapy - treat on suspicion, do not wait for the antibody result

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