Autoimmune necrotizing myopathy is an inflammatory myopathy characterized by prominent myofiber necrosis with minimal inflammatory cell infiltration, often associated with anti-SRP or anti-HMGCR antibodies, leading to progressive proximal muscle weakness.

Exam domain	One-glance essentials
Definition / diagnosis	Immune-mediated necrotizing myopathy (IMNM) causes prominent myofibre necrosis/regeneration with minimal lymphocytic inflammation ^[1]^[2] Main serotypes: anti-SRP, anti-HMGCR and seronegative IMNM ^[2]
Epidemiology / risks	Statin exposure is strongly linked to anti-HMGCR disease, but statin-naïve cases occur ^[1]^[2] Seronegative/older-onset disease warrants malignancy assessment; NPC is locally relevant ^[2]
Core mechanism	Autoantibody binding + complement/MAC activation → sarcolemmal rupture → massive CK release ^[2] Regenerating fibres overexpress HMGCR → self-perpetuating autoimmune injury even after statin withdrawal
Clinical picture	Rapid/subacute symmetric proximal weakness with no DM rash; CK often > 10× ULN ^[1]^[2] Neck flexor, bulbar or respiratory weakness and dark urine mark severe disease; anti-SRP disease may involve heart ^[2]
Investigations	CK, anti-HMGCR/anti-SRP, EMG and MRI-STIR define active myopathy and guide biopsy ^[2] Biopsy: necrosis + regeneration + macrophages, sparse lymphocytes, sarcolemmal C5b-9; no perifascicular atrophy/rimmed vacuoles ^[2] Screen swallowing, ECG/echo, PFT/HRCT and malignancy
Management	Stop statins permanently; begin high-dose glucocorticoid plus an early steroid-sparing agent ^[2]^[3] Refractory/severe disease: IVIG and/or rituximab; anti-SRP often needs early escalation ^[2]^[3] Physiotherapy and swallowing/respiratory support are integral
Complications	Dysphagia → aspiration; respiratory weakness → ventilatory failure; rhabdomyolysis → AKI/hyperkalaemia ^[2] Myocarditis/cardiomyopathy (especially anti-SRP) and irreversible fatty muscle replacement may occur ^[2]
Prevention / follow-up	Monitor CK, power, swallowing and FVC; treat early before fatty replacement ^[2] Screen HBV/TB and vaccinate before immunosuppression; provide PJP and bone prophylaxis when indicated ^[3] Repeat cancer surveillance in high-risk/seronegative disease
Exam traps	Toxic statin myopathy improves after stopping statin; anti-HMGCR IMNM persists ^[2] Worsening weakness on steroids: rising CK = relapse; normal CK = steroid myopathy ^[2] Anti-SRP/HMGCR + necrotizing biopsy is IMNM, not polymyositis

References

^[1] Senior notes: Maksim Medicine Notes.pdf (Idiopathic inflammatory myopathies, p. 318) ^[2] Senior notes: Ryan Ho Neurology.pdf (Inflammatory Myopathies, pp. 191–195); Ryan Ho Rheumatology.pdf (pp. 91–92) ^[3] Lecture slides: Block A - Rheumatology Interactive Tutorial.pdf (myositis management and screening)

Autoimmune Necrotizing Myopathy (AINM / IMNM)

Autoimmune necrotizing myopathy (ANM) — also called immune-mediated necrotizing myopathy (IMNM) — is a subtype of the idiopathic inflammatory myopathies (IIM) characterised histopathologically by prominent myofibre necrosis and regeneration with minimal or absent inflammatory cell infiltration in skeletal muscle ^[1]^[2]. Unlike classical polymyositis or dermatomyositis where T-cell or perivascular inflammatory infiltrates dominate, the hallmark of IMNM is antibody- and complement-mediated destruction of muscle fibres rather than a cell-mediated autoimmune attack.

Breaking down the name:

Auto-immune = the immune system attacks "self" tissue

Necrotizing (Greek nekros = death) = myofibre death/necrosis is the dominant pathological finding

Myopathy (Greek myo = muscle, pathos = disease) = disease of muscle

This distinction is clinically important because IMNM tends to be more severe, more refractory to treatment, and has a different autoantibody profile compared to other inflammatory myopathies ^[1]^[2].

Key Distinction from Polymyositis

IMNM was historically lumped under "polymyositis," but it is now recognised as a separate entity. On muscle biopsy, polymyositis shows endomysial CD8+ T-cell infiltrates surrounding and invading non-necrotic fibres, whereas IMNM shows scattered necrotic and regenerating fibres with macrophage predominance and sparse lymphocytic infiltration. This has direct therapeutic implications — IMNM often requires more aggressive immunosuppression ^[1]^[2].

Parameter	Detail
Incidence	~20% of all IIM cases; rare overall (IIM incidence ~2–10/million/year)
Age of onset	Bimodal — can occur at any age but peaks in adults 40–60 years; anti-SRP+ tends to present younger (30–50 years), anti-HMGCR+ older (> 50 years)
Sex	Female predominance overall (F:M ≈ 2:1); anti-HMGCR+ IMNM shows less female predominance
Geography	Anti-HMGCR+ IMNM is increasingly recognised worldwide due to widespread statin use. In Hong Kong, statin prescriptions are very common for the ageing population, making this a relevant clinical entity
Racial variation	Anti-SRP+ IMNM may be more common and more severe in African Americans

Risk Factors

Statin use — the strongest and most clinically important association
- Statins (HMG-CoA reductase inhibitors) can trigger anti-HMGCR antibody production
- Mechanism: statins upregulate HMGCR expression in regenerating myofibres → HMGCR becomes an autoantigen → autoimmune attack perpetuates even after statin withdrawal
- Not all statin myopathy is IMNM — most statin-related muscle symptoms are self-limiting toxic myopathy that resolves on discontinuation. IMNM is the autoimmune form that persists
- ~60–70% of anti-HMGCR+ IMNM patients have prior statin exposure, but 30–40% develop it without ever taking statins (particularly younger patients and children)
Malignancy — IMNM can be cancer-associated, particularly in seronegative IMNM and in older patients ^[1]^[2]
- Types: adenocarcinoma of cervix, lung, ovaries, pancreas, bladder, stomach, NPC (this locality) ^[2]
- Temporal relationship: can be diagnosed before, with or after diagnosis of inflammatory myopathy ^[2]
Connective tissue disease overlap — can occur in the context of other autoimmune conditions
Genetic predisposition — HLA-DRB111:01 associated with anti-HMGCR+ IMNM; HLA-DRB108:03 associated with anti-SRP+ IMNM

Hong Kong context: Given the high prevalence of statin prescriptions for dyslipidaemia and cardiovascular risk reduction in our ageing population, and the local prevalence of NPC (nasopharyngeal carcinoma), clinicians in HK should have a low threshold for considering IMNM in a patient on statins who develops persistent proximal weakness, and should perform NPC screening (including EBV serology and nasopharyngoscopy) as part of the malignancy workup ^[2].

3. Anatomy and Function: The Skeletal Muscle

Understanding why IMNM presents as it does requires understanding normal skeletal muscle anatomy:

Motor unit = a lower motor neuron + all the muscle fibres it innervates
Muscle fibres are organised into fascicles (bundles wrapped in perimysium), and each fibre is surrounded by endomysium
Each muscle fibre (cell) is a multinucleated syncytium with peripherally located nuclei
The sarcolemma (cell membrane) contains ion channels, receptors, and structural proteins (dystrophin, etc.)
Inside: myofibrils composed of repeating sarcomeres (actin + myosin = the contractile machinery)

Proximal muscles (shoulder girdle, hip girdle) are larger, more metabolically active, and have higher energy demands
They are therefore more vulnerable to:
- Inflammatory/immune-mediated damage
- Metabolic insults
- Ischaemic injury from capillary dropout
This is why patients struggle with tasks requiring proximal strength: climbing stairs, rising from a chair, combing hair, reaching overhead

Creatine kinase (CK) is the most abundant intracellular enzyme in skeletal muscle
When myofibres are damaged (necrosis), CK leaks into the bloodstream → CK is typically markedly elevated in IMNM, often > 10× ULN, sometimes > 50× ULN ^[1]^[2]
Other enzymes: LDH, AST, ALT, aldolase also leak out (AST/ALT elevation may be mistakenly attributed to liver disease)

4. Aetiology and Pathophysiology

IMNM is classified by serological subtype (based on autoantibodies), which is the most clinically useful framework:

Subtype	Autoantibody	Approximate Proportion	Key Associations
Anti-SRP+ IMNM	Anti-signal recognition particle (SRP)	~30–40% of IMNM	More severe, refractory disease; younger onset; cardiac involvement; aggressive disease refractory to high-dose steroids and immunosuppressants ^[3]
Anti-HMGCR+ IMNM	Anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR)	~30–40% of IMNM	Statin exposure in majority; older patients; can occur without statins
Seronegative IMNM	Neither anti-SRP nor anti-HMGCR	~20–30% of IMNM	Higher malignancy association; may overlap with other CTD; more heterogeneous

High Yield — Autoantibody-defined Subsets

Anti-SRP antibody defines a subset with severe myopathy with muscle fibre necrosis / endomysial fibrosis with minimal inflammatory infiltrates on histology, and aggressive disease refractory to high-dose steroids and immunosuppressants ^[3].

Anti-HMGCR antibody identifies statin-triggered autoimmune myopathy — the disease does not resolve with statin cessation (unlike toxic statin myopathy) because the autoimmune process has become self-perpetuating.

Note that autoAb defines homogeneous clinical subsets of disease ^[3].

4.2 Pathophysiology — From First Principles

Anti-HMGCR+ pathway:

Patient takes a statin → statin inhibits HMG-CoA reductase (HMGCR) in hepatocytes (intended therapeutic effect)
Statins also cause upregulation of HMGCR protein expression in muscle fibres (compensatory response to enzyme inhibition)
In genetically susceptible individuals (HLA-DRB1*11:01), the overexpressed HMGCR is presented as a neoantigen by MHC class II → loss of immune tolerance → generation of anti-HMGCR autoantibodies
These antibodies bind HMGCR on the sarcolemma of muscle fibres → activate complement → membrane attack complex (MAC) formation on myofibres → myofibre necrosis
Necrotic fibres undergo regeneration → regenerating fibres express even more HMGCR → more antigen presentation → self-amplifying cycle of destruction and regeneration
This is why stopping the statin does not stop the disease — the autoimmune loop is self-perpetuating

Anti-SRP+ pathway:

Signal recognition particle (SRP) is an intracellular ribonucleoprotein involved in targeting nascent proteins to the endoplasmic reticulum
Mechanism of loss of tolerance to SRP is less well understood — possibly triggered by viral infection or other immune activation events
Anti-SRP antibodies may directly bind muscle fibres, activate complement, and cause severe necrosis
Histologically: severe myopathy with muscle fibre necrosis / endomysial fibrosis with minimal inflammatory infiltrates ^[3]

The dominant effector mechanism in IMNM is humoral (antibody-mediated) rather than cell-mediated:

Key pathological features explained:

Necrotic fibres: pale, eosinophilic, loss of cross-striation → direct complement-mediated killing
Regenerating fibres: basophilic, centrally located nuclei → attempted repair
Macrophage-predominant infiltration: macrophages phagocytose necrotic debris (this is clean-up, not the primary attack)
Sparse T-cell infiltrates: this distinguishes IMNM from polymyositis where CD8+ T cells are the primary effectors
MAC (C5b-9) deposition on non-necrotic fibres: visible on immunohistochemistry — this is a characteristic finding
Capillary involvement: anti-SRP+ IMNM may show pipestem capillaries (capillary wall thickening) but not the perifascicular atrophy seen in dermatomyositis

If untreated or refractory:

Repeated cycles of necrosis → regeneration → necrosis
Eventually fatty replacement and fibrosis of muscle (seen on MRI as T1 hyperintensity)
Irreversible weakness if treatment is delayed
This is why early diagnosis and aggressive treatment are essential

Why IMNM Has Very High CK Levels

Because the pathology is direct myofibre necrosis (sarcolemma rupture by MAC), CK leaks massively. In contrast, in dermatomyositis where the primary target is intramuscular vasculature (causing ischaemic damage), CK may be only moderately elevated. In IBM, CK is often only mildly elevated because the process is slow and chronic. IMNM typically has the highest CK among all IIMs (often > 5,000–10,000 U/L, sometimes > 50,000 U/L).

5. Classification

Idiopathic inflammatory myopathies are classified as ^[1]^[2]:

Subtype	Key Features
Dermatomyositis (DM)	Characteristic skin rash + proximal weakness; perifascicular atrophy on biopsy; anti-Mi2, anti-MDA5, anti-NXP2, anti-TIF1γ
Polymyositis (PM)	Proximal weakness without skin rash; endomysial CD8+ T-cell infiltration; diagnosis of exclusion (increasingly rare as a standalone diagnosis)
Inclusion body myositis (IBM)	Very rare in HK; proximal + distal muscle weakness; failed response to treatment; Dx inclusion bodies in muscle biopsy ^[1]
Autoimmune necrotizing myopathy (IMNM/AINM)	Prominent necrosis, minimal inflammation; anti-SRP or anti-HMGCR; often severe and refractory
Overlap myositis	When a/w collagen vascular disease ^[2]; anti-synthetase syndrome now often classified here
Cancer-associated myositis (CAM)	Can occur with any IIM subtype; DM > PM in malignancy risk
Clinically amyopathic dermatomyositis (CADM)	Cutaneous manifestations, but no muscle weakness for ≥6 months ^[1]; anti-MDA5

High Yield — GC Lecture Classification

Brief introduction on the subtypes of IIM: Dermatomyositis, Polymyositis, Anti-synthetase syndrome, Immune-mediated necrotizing myopathy ^[4]. This is from the GC rheumatology interactive tutorial and represents the examinable classification framework.

Feature	Anti-SRP+ IMNM	Anti-HMGCR+ IMNM	Seronegative IMNM
Age of onset	Younger (30–50 y)	Older (> 50 y)	Variable
Statin association	No	Yes (~60–70%)	No
CK level	Very high (often > 10,000)	High (often > 5,000)	Variable
Severity	Severe, refractory ^[3]	Moderate to severe	Variable
Cardiac involvement	More common	Less common	Variable
ILD	Uncommon	Rare	Uncommon
Malignancy risk	Low	Low–moderate (esp. if statin-naïve)	Highest among IMNM subtypes
Skin manifestations	Seldom have skin manifestations ^[3]	None	None
Response to treatment	Aggressive disease refractory to high-dose steroids and immunosuppressants ^[3]	Moderate response	Variable
Histology	Necrosis + fibrosis, minimal inflammation	Necrosis + regeneration, MAC deposition	Necrosis, macrophage infiltration

6. Clinical Features

Symptom	Pathophysiological Basis	Notes
Progressive proximal muscle weakness	Necrosis of proximal muscle fibres (shoulder/hip girdle) → loss of contractile units	Symmetrical weakness in shoulder girdle + hip girdle ^[1]; difficulty rising from chairs, climbing stairs, lifting arms overhead, combing hair
Rapid onset (days to weeks in severe cases)	Acute complement-mediated necrosis → rapid destruction	Faster progression than DM/PM in many anti-SRP+ cases
Myalgia (muscle pain)	Necrotic fibres release inflammatory mediators (prostaglandins, bradykinin) → nociceptor activation	± pain (if acute, usually mild) ^[2]; pain is NOT a dominant feature — weakness is
Dysphagia	Bulbar muscle involvement ^[1] — pharyngeal and oesophageal striated muscle weakness → impaired swallowing	Dysphagia, dysphonia, HOV (hoarseness of voice) ^[1]; can lead to aspiration
Dysphonia / Hoarseness of voice	Weakness of laryngeal muscles	Less common but characteristic of severe disease
Dyspnoea	(1) Respiratory muscle weakness (diaphragm, intercostals) → hypoventilation; (2) Rare ILD (more common in anti-synthetase); (3) Cardiac involvement in anti-SRP+	Ask about exertional dyspnoea, orthopnoea
Fatigue	Generalised muscle dysfunction + systemic inflammation	Non-specific but very common
Dark urine	Myoglobinuria from massive muscle necrosis (rhabdomyolysis) → myoglobin excreted in urine	"Cola-coloured urine" — indicates severe disease; risk of AKI
Arthralgia	Systemic autoimmune inflammation; overlap with CTD features	Less prominent than in antisynthetase syndrome

What Patients Cannot Do — Functional Impact

Cannot rise from a squat or low chair without using arms
Cannot climb stairs
Cannot lift arms above head (combing hair, reaching shelves)
Cannot lift head off pillow (neck flexor weakness — a red flag for severity)
In severe cases: cannot swallow (choking episodes), cannot breathe adequately

Difficulty in swallowing food with episodes of choking — this is a key clinical scenario from the GC interactive tutorial case ^[4].

Sign	Pathophysiological Basis	Notes
Proximal muscle weakness on examination	Direct necrosis of proximal muscle groups	MRC grading: often grade 3–4/5 proximally; distal strength relatively preserved (unlike IBM)
Neck flexor weakness	Anterior neck flexors are a "semi-proximal" group frequently affected in IIM	Test: ask patient to lift head against resistance while supine — a bedside test for severity
Intact sensation	The disease targets muscle, not peripheral nerves	Normal sensory examination helps distinguish from neuropathy
Normal or depressed deep tendon reflexes	Reflex arc involves muscle contraction — weakened muscle produces weaker contraction; no UMN involvement	NOT brisk (would suggest UMN pathology)
No fasciculations	Fasciculations indicate LMN denervation (anterior horn cell disease); IMNM is a myopathic process	Helps distinguish from motor neuron disease
No skin rash	IMNM typically lacks the cutaneous features of dermatomyositis	Anti-SRP is almost exclusively described in polymyositis, i.e. seldom have skin manifestations ^[3]. No heliotrope rash, no Gottron's papules
Muscle wasting (late finding)	± wasting/contractures (ONLY if chronic) ^[2] — chronic cycles of necrosis → fatty/fibrotic replacement	Not present early; indicates delayed diagnosis or refractory disease
Muscle tenderness	Acute necrotic fibres release inflammatory mediators	Variable; may be mild or absent
Raynaud's phenomenon	If overlap with CTD features; vasospasm of digital arteries → white (ischaemia) → blue (cyanosis) → red (reactive hyperaemia)	Pain and numbness of fingers on exposure to cold ^[4]

System	Manifestation	Mechanism	IMNM Subtype Most Affected
Cardiac	Myocarditis, cardiomyopathy, arrhythmias, heart failure	Antibody/complement-mediated damage to cardiac myocytes (which also express the target antigens)	Anti-SRP+ (more common)
Pulmonary	ILD (≥10%): a/w anti-Jo1 Ab (anti-synthetase) ^[3]; respiratory muscle weakness → hypoventilation	ILD: autoimmune alveolitis; hypoventilation: diaphragm weakness	ILD is uncommon in pure IMNM; more common in overlap/antisynthetase
Oesophageal	Dysphagia, nasal regurgitation, aspiration, aspiration pneumonia ^[3]	Striated muscle of upper oesophagus affected	All subtypes
Renal	AKI from rhabdomyolysis → myoglobin cast nephropathy	Massive CK elevation → myoglobinuria → tubular obstruction and injury	Severe anti-SRP+ cases
Joints	Arthralgia, non-erosive arthritis	Systemic autoimmune inflammation	Overlap cases

High Yield — Cancer Association in IIM

Adult form a/w malignancy: 5× risk in dermatomyositis, 2× risk in polymyositis ^[2]. IMNM (particularly seronegative) also has an increased malignancy risk.

1/3 malignancy (lung, breast, gastric, NPC) – usually diagnosed within 1 year of DM/PM ^[1].

In Hong Kong, NPC screening is essential. Always think about this in any new IIM diagnosis.

Malignancy can occur before, with, or after onset of inflammatory myopathy ^[2]^[3].

7. Distinguishing IMNM from Other Causes of Proximal Weakness

This is critical for clinical approach. When you see a patient with proximal muscle weakness, the differential is broad:

Feature	IMNM	Dermatomyositis	Polymyositis	IBM
Skin rash	Absent	Heliotrope, Gottron's, shawl/V sign ^[1]	Absent	Absent
CK level	Very high (often > 10×)	Moderate	Moderate–high	Normal–mildly elevated
Weakness pattern	Symmetric proximal	Symmetric proximal	Symmetric proximal	Proximal + distal ^[1]
Onset speed	Can be rapid	Subacute	Subacute	Insidious (years)
Biopsy	Necrosis + regeneration, minimal inflammation, MAC	Perifascicular atrophy, perivascular B/CD4+ T cells	Endomysial CD8+ T cells invading non-necrotic fibres	Rimmed vacuoles, inclusion bodies, endomysial CD8+
Treatment response	Often refractory (esp. anti-SRP+) ^[3]	Usually responds	Usually responds	Failed response to treatment ^[1]
Autoantibodies	Anti-SRP, anti-HMGCR	Anti-Mi2, anti-MDA5, anti-TIF1γ, anti-NXP2	Non-specific	None (anti-cN1A in some)

8. Clinical Approach to a Patient with Suspected IMNM

Characterise the weakness:
- Onset and duration (acute/subacute/chronic?)
- Distribution (proximal vs distal vs both?)
- Progression (getting worse? stable? fluctuating?)
- Functional impact (stairs, rising from chair, combing hair, swallowing?)
Ask about associated symptoms:
- Skin rash? (→ DM)
- Dysphagia, choking? (→ bulbar involvement)
- Dyspnoea? (→ respiratory muscle weakness, ILD, cardiac)
- Dark urine? (→ rhabdomyolysis)
- Joint pain? Raynaud's? Dry eyes/mouth? (→ CTD overlap)
- Fever? Weight loss? (→ malignancy, antisynthetase)
Drug history ^[5]:
- Statins — most important! Which statin, duration, timing of onset relative to statin initiation
- Other myotoxic drugs: fibrates, colchicine, hydroxychloroquine, checkpoint inhibitors (pembrolizumab, nivolumab)
- Methotrexate lung → hypersensitivity reaction from csDMARD ^[5] (if patient is on immunosuppressants for other reasons)
- NSAIDs → GI bleeding ^[5] (relevant for anaemia workup)
Past medical history:
- Prior malignancy? (the GC case mentions history of breast cancer 5 years ago ^[4])
- Other autoimmune diseases?
- Family history of autoimmune or neuromuscular disease?
Cancer red flags (especially in older patients):
- Weight loss, night sweats, constitutional symptoms
- New lumps, bleeding, change in bowel habit
- In Hong Kong: epistaxis, nasal obstruction, hearing loss (NPC)

General inspection: muscle bulk (wasting?), skin (rash? — should be absent in pure IMNM)
Power testing (MRC grading):
- Neck flexors (lift head off pillow)
- Shoulder abduction and flexion (deltoid)
- Hip flexion (iliopsoas)
- Compare proximal vs distal
Reflexes: normal or reduced (myopathic pattern)
Sensation: should be intact
Swallowing assessment: if dysphagia reported
Respiratory: respiratory rate, use of accessory muscles, chest expansion
Cardiovascular: signs of heart failure (if cardiac involvement)
Full systemic examination: looking for malignancy, other CTD features

Conditions that are associated with Raynaud's phenomenon: connective tissue disease patients often present with multi-system complaints ^[4].

High Yield Summary

Autoimmune Necrotizing Myopathy (IMNM) — Key Points:

Definition: Subtype of IIM characterised by myofibre necrosis with minimal inflammation on biopsy, distinct from PM/DM
Pathophysiology: Antibody + complement-mediated (humoral), NOT T-cell mediated → MAC deposition → sarcolemma rupture → massive CK elevation
Three subtypes by autoantibody: Anti-SRP+ (severe, refractory), Anti-HMGCR+ (statin-associated), Seronegative (highest malignancy risk)
Clinical features: Symmetric proximal weakness, very high CK (often > 10× ULN), NO skin rash, may have dysphagia and cardiac involvement
Statin association: Anti-HMGCR+ IMNM — statin upregulates HMGCR → neoantigen → autoimmune cycle that persists after statin withdrawal
Cancer screening essential: Especially NPC in Hong Kong; malignancy can occur before, with, or after onset ^[2]
Anti-SRP+: Aggressive disease refractory to high-dose steroids and immunosuppressants ^[3]
Distinguish from: DM (skin rash), PM (CD8+ T-cell infiltrate on biopsy), IBM (distal weakness, non-responsive, inclusion bodies), toxic statin myopathy (resolves with statin cessation)

Active Recall - Autoimmune Necrotizing Myopathy

Differential Diagnosis of Autoimmune Necrotizing Myopathy

When a patient walks into clinic — or, more likely, struggles to walk in — with progressive proximal muscle weakness and a markedly elevated CK, your job is not simply to label it "myopathy" and move on. You need a systematic framework to localise the lesion, stratify the differential, and then narrow it down. IMNM sits within a broader landscape of conditions that can mimic it. Let's work through this from first principles.

Before diving into the differential for IMNM specifically, recall that "weakness" can originate from any level of the neuraxis. The first clinical step is always localisation ^[6].

I learned to approach lower limb weakness by first localizing the lesion anatomically, asking whether it involves the cerebrum, brainstem, spinal cord, anterior horn cells, nerve roots, peripheral nerves, neuromuscular junction, or muscle. Key discriminating features include distribution of weakness, presence of upper versus lower motor neuron signs, sensory involvement, sphincter disturbances, and cortical signs ^[6].

The key "red line" for IMNM is: proximal weakness + very high CK + NO skin rash + NO sensory loss + NO UMN signs + biopsy showing necrosis without significant inflammation.

2. Differential Diagnosis of IMNM — Systematic Categorisation

The differential can be organised using the classic "VITAMIN-CDE" sieve adapted for myopathy, as presented across multiple sources ^[7]^[8]^[9]:

High Yield — GC Lecture Slide: Differential Diagnosis of Myopathy

From the GC neurology lecture ^[7]:

Category	Examples
Infective	Viral (HIV, CMV, EBV…), pyomyositis
Neoplastic	Paraneoplastic
Inflammatory	Rheumatoid arthritis, Sjögren's syndrome
Congenital	Muscular dystrophy
Autoimmune	Dermatomyositis, necrotising autoimmune myositis
Trauma / toxin	Crush injuries / seizures causing rhabdomyolysis, glucocorticoids, colchicine, statins
Endocrine	Hypothyroidism, Cushing's syndrome, hypokalemia

This is a high-yield exam table — know this categorisation.

Let me now expand each category, explaining why each mimics IMNM and how to distinguish them.

2A. Other Idiopathic Inflammatory Myopathies (IIMs)

These are the closest mimics because they share the core feature of autoimmune proximal weakness with elevated CK.

Feature	How It Differs from IMNM
Cutaneous manifestations — usually appear before myopathy ^[1]	IMNM has NO skin rash. DM has heliotrope rash, Gottron's papules, shawl sign and V sign, mechanic's hands, holster's sign, calcinosis cutis, dilated nailfold capillaries ^[1]
CK	Moderate elevation (often < 10× ULN) vs IMNM's very high CK
Biopsy	Perifascicular atrophy, perivascular B cells and CD4+ T cells, complement deposition on capillaries ^[9] vs IMNM's necrosis with minimal inflammation
Autoantibodies	Anti-Mi2 (classic DM, good prognosis), anti-MDA5 (CADM + rapidly progressive ILD), anti-TIF1γ/anti-NXP2 (cancer-associated) vs anti-SRP/anti-HMGCR in IMNM
Cancer risk	5× risk in dermatomyositis ^[2]^[3] — higher than IMNM overall

Why the confusion arises: Both cause symmetric proximal weakness. But if there is NO rash, you cannot call it DM. The old habit of labelling everything without rash as "polymyositis" has led to many IMNM cases being misclassified.

Feature	How It Differs from IMNM
Biopsy	Cellular infiltrate is predominantly within the fascicle with inflammatory cells invading individual muscle fibers; ↑ Cytotoxic CD8+ T lymphocytes; NO signs of vasculopathy ^[9] — this is a T-cell mediated attack on individual fibres. IMNM is antibody/complement-mediated necrosis
CK	Moderate–high, but rarely as extreme as IMNM
Treatment response	Generally responds to steroids better than anti-SRP+ IMNM
Current status	PM as a standalone entity is increasingly questioned; many previously labelled PM cases are now reclassified as IMNM, IBM, or anti-synthetase syndrome

Why the confusion arises: Before myositis-specific antibodies were available, anything without a rash was called PM. Now, muscle biopsy and autoantibodies allow proper reclassification.

Feature	How It Differs from IMNM
Age	Typically > 50 years, male predominance
Weakness pattern	Proximal + distal muscle weakness ^[1] — specifically finger flexors (grip weakness) and quadriceps → asymmetric! This is very different from IMNM's purely proximal symmetric weakness
CK	Normal to mildly elevated (rarely > 5× ULN) — much lower than IMNM
Biopsy	Rimmed vacuoles, inclusion bodies ^[1], endomysial CD8+ T-cell infiltrates PLUS degenerative features
Treatment	Failed response to treatment ^[1] — does NOT respond to immunosuppression, unlike IMNM which at least partially responds
Onset	Insidious (years) — IBM creeps up over months to years, unlike IMNM which can be subacute ^[8]

IBM vs IMNM — A Common Exam Trap

IBM is the inflammatory myopathy commonly misdiagnosed as PM ^[8]. Students often confuse IBM with IMNM because both lack skin rash. The distinguishing features are: IBM has distal involvement (finger flexors, quadriceps), low CK, insidious onset, rimmed vacuoles on biopsy, and does NOT respond to immunosuppression. IMNM has purely proximal weakness, very high CK, and necrosis without vacuoles on biopsy.

Feature	How It Differs from IMNM
Autoantibody	Anti-Jo1 (most common), anti-PL7, anti-PL12, anti-EJ, anti-OJ
Clinical features	Classic triad/pentad: myositis + ILD + mechanic's hands + Raynaud's + non-erosive arthritis + fever ^[3]
ILD	Very common (> 70%) and may be the dominant feature — vs ILD being uncommon in pure IMNM
Biopsy	Perifascicular necrosis + perimysial inflammation — differs from IMNM's scattered necrosis
Skin	Mechanic's hands: hyperkeratotic, fissured skin on palmar and lateral aspects of fingers ^[3]

Why the confusion arises: Anti-synthetase syndrome involves myositis, so CK is elevated and there is proximal weakness. But the prominent ILD, mechanic's hands, and arthritis set it apart.

When a/w collagen vascular disease ^[2] — the myositis occurs in context of SLE, systemic sclerosis (SSc), MCTD, RA, or Sjögren's
Distinguished by features of the underlying CTD (malar rash for SLE, skin thickening for SSc, etc.)
Myositis-associated autoantibodies (suggestive of other CTDs): anti-Ro, anti-La, anti-Sm, anti-RNP ^[10]

2B. Drug-Induced Myopathy

This is the most important practical differential for anti-HMGCR+ IMNM, because the initial question is always: "Is this just statin toxicity, or is this true autoimmune disease?"

Feature	Statin Toxic Myopathy	Anti-HMGCR+ IMNM
Mechanism	Direct pharmacological toxicity (mitochondrial dysfunction, coenzyme Q10 depletion)	Autoimmune — anti-HMGCR antibodies + complement
CK level	Usually < 10× ULN; may be normal with myalgia only	Usually > 10× ULN, often > 50×
Response to statin withdrawal	Resolves within days to weeks	Does NOT resolve — persists or worsens
Anti-HMGCR antibody	Negative	Positive
Biopsy	Non-specific type II fibre atrophy; no necrosis	Necrosis, regeneration, MAC deposition

The key teaching point: If you stop the statin and the patient improves → toxic myopathy. If you stop the statin and weakness persists or CK stays high → think IMNM, check anti-HMGCR antibody.

Drug	Mechanism	Key Clues
Glucocorticoids ^[7]^[8]	Type IIb fibre atrophy (catabolic effect on muscle protein); NO inflammation, NO CK elevation	Proximal weakness with normal CK; temporal relationship with steroid use; Cushing's features
Colchicine ^[7]	Disrupts microtubules → vacuolar myopathy; often combined with neuropathy	Concomitant neuropathy (neuromyopathy); typically in patients with CKD (reduced clearance)
Hydroxychloroquine	Lysosomal dysfunction → vacuolar myopathy	Very long-term use; curvilinear bodies on biopsy
Checkpoint inhibitors (pembrolizumab, nivolumab)	Immune-mediated — can trigger IMNM-like picture	Oncology patients; temporally related to immunotherapy initiation
Fibrates	Similar to statins; additive risk when combined	Check drug interactions
Zidovudine (AZT)	Mitochondrial myopathy	HIV patients; ragged red fibres on biopsy

Steroid Myopathy — The Ironic Trap

Glucocorticoid-induced myopathy ^[7]^[8] is particularly tricky because steroids are used to TREAT inflammatory myopathies. A patient on high-dose prednisolone who develops worsening proximal weakness might have (a) relapsing IMNM, or (b) steroid myopathy. The key distinguishing feature: CK is NORMAL in steroid myopathy (because there is no necrosis, just atrophy) but CK is elevated in active IMNM. This distinction guides whether to increase or decrease the steroid dose — a critical clinical decision.

These are systemic conditions where proximal weakness is a secondary feature.

Condition	Mechanism	Key Distinguishing Features
Hypothyroidism ^[7]^[8]	Reduced metabolic rate → impaired muscle energy metabolism; ↓Na⁺/K⁺-ATPase activity; accumulation of glycosaminoglycans in muscle	Myopathy associated with hypothyroidism can mimic inflammatory myopathy with a subacute onset of proximal muscle weakness and elevated CK ^[8]; but patient also has fatigue, cold intolerance, constipation, weight gain, delayed relaxation of reflexes; check TFT
Cushing's syndrome ^[7]^[9]	Glucocorticoid excess → protein catabolism, type IIb fibre atrophy	Proximal weakness with normal CK; cushingoid habitus; moon face, striae, central obesity
Hypokalemia ^[7]^[9]	K⁺ depletion → muscle cell hyperpolarisation → impaired depolarisation and contraction	Muscle weakness, paralysis (proximal muscle myopathy); rhabdomyolysis ^[11]; check serum K⁺; episodic weakness; ECG changes (U waves, flattened T waves)
Hypophosphataemia	Phosphate depletion → impaired ATP synthesis → energy failure in muscle	Chronic alcoholism, refeeding syndrome, diabetic ketoacidosis recovery
Hypercalcaemia	↑Ca²⁺ impairs neuromuscular transmission and muscle contractility	Check serum Ca²⁺; associated lethargy, confusion, constipation

Why these matter: All are treatable causes that must be excluded before committing to an IMNM diagnosis. A simple TFT and electrolyte panel rules out most of them. The GC lecture on myopathy explicitly lists hypothyroidism, Cushing's syndrome, and hypokalemia as endocrine differentials ^[7].

Agent	Mechanism	Key Distinguishing Features
Viral: HIV, CMV, EBV, influenza, Coxsackie ^[7]^[9]	Direct viral invasion of myocytes → inflammation and necrosis	Acute febrile illness; self-limiting; diffuse myalgia > weakness; check viral serology
Pyomyositis (Staph. aureus)	Bacterial abscess within muscle	Localised pain, swelling, fever; often in immunocompromised; MRI shows focal abscess
Parasitic: Trichinella, Toxoplasma	Larval/parasite invasion of muscle	Travel history; eosinophilia; periorbital oedema (trichinosis)

Why the confusion arises: Viral myositis can cause elevated CK and diffuse weakness, but it is typically acute, self-limiting, and associated with a systemic viral syndrome. IMNM is subacute to chronic and progressive.

Myasthenia Gravis (MG)

Feature	How It Differs from IMNM
Mechanism	NMJ post-synaptic disorder caused by antibodies to ACh receptors ^[8] — blocks neuromuscular transmission
Weakness character	Fatigable — gets worse with repetitive use, improves with rest; this is the hallmark
Distribution	Facial muscle weakness ^[8] (ptosis, diplopia, dysphagia) — ocular involvement is very common
CK	Normal muscle enzymes ^[8]
EMG	Decremental response on repetitive nerve stimulation ^[8]; IMNM shows myopathic potentials
Autoantibodies	AChR antibodies ^[8] or anti-MuSK

Why the confusion arises: Both cause proximal and bulbar weakness (dysphagia). But MG has fatigability, ocular involvement, and normal CK. IMNM has constant weakness, typically spares eyes, and has very high CK.

Condition	Key Distinguishing Features from IMNM
Muscular dystrophy (Duchenne, Becker, limb-girdle) ^[7]^[8]^[9]	Inherited group of progressive myopathic disorders resulting from defects in genes required for normal muscle function ^[8]; positive family history; childhood/adolescent onset (DMD/BMD); elevated CK but genetic testing is diagnostic; biopsy shows dystrophic changes, not necrosis-regeneration with MAC
Myotonic dystrophy ^[5]^[8]	Proximal myotonic myopathy (PROMM) presents with myotonia, slowed relaxation following a normal muscle contraction and positive family history ^[8]; distal weakness + wasting in classic DM1 (temporalis, sternocleidomastoid, forearms); myotonia (delayed relaxation); multisystem (cataracts, cardiac conduction defects, DM, testicular atrophy) ^[5]; genetic testing (CTG repeat expansion)
Metabolic myopathies (glycogen storage, lipid storage, mitochondrial)	Episodic weakness or exercise intolerance; second-wind phenomenon (McArdle disease); ragged red fibres on biopsy (mitochondrial); specific enzyme assays

Why the confusion arises: Limb-girdle muscular dystrophy (LGMD) can present in adulthood with proximal weakness and elevated CK — closely mimicking IMNM. Genetic testing and biopsy are essential for differentiation.

Muscular Dystrophy Mimicking IMNM

An adult presenting with proximal weakness and high CK may have late-onset LGMD. Key clues pointing away from IMNM: family history of similar weakness, very slowly progressive course (years), absence of myositis-specific autoantibodies, and dystrophic features on biopsy (not pure necrosis-regeneration). Always consider genetic myopathies in the differential, especially if immunosuppressive treatment fails.

Feature	How It Differs from IMNM
Weakness pattern	Both UMN AND LMN signs (brisk reflexes + fasciculations + wasting); IMNM has neither UMN signs nor fasciculations
Fasciculations	Present in MND; absent in IMNM
CK	Can be mildly elevated in MND (from denervation), but not massively elevated
EMG	Denervation pattern (fibrillation + fasciculation + large motor unit potentials); IMNM shows myopathic pattern (small, polyphasic, short-duration potentials)
Sensory	Normal in both

Paraneoplastic ^[7] myopathy can manifest as proximal weakness in the context of an occult malignancy, sometimes independent of direct IIM. However, IMNM itself (especially seronegative) can BE the paraneoplastic manifestation. This creates conceptual overlap.

Adult form a/w malignancy: 5× risk in dermatomyositis, 2× risk in polymyositis ^[2]^[3]
Types: adenocarcinoma of cervix, lung, ovaries, pancreas, bladder, stomach, NPC (this locality) ^[2]^[3]
Temporal relationship: can be diagnosed before, with or after diagnosis of inflammatory myopathy ^[2]^[3]
Potential association between cancer and dermatomyositis and the rationale of cancer screening ^[4]
In seronegative IMNM patients, the malignancy association is highest — always perform a thorough malignancy screen

Cause	Mechanism	Distinguishing from IMNM
Crush injuries / seizures ^[7]	Mechanical destruction of muscle	History of trauma, prolonged immobilisation, seizure
Severe exercise (exertional rhabdomyolysis)	Energy depletion → sarcolemma rupture	History of extreme physical exertion
Drugs / toxins (statins, alcohol, cocaine, amphetamines)	Direct myotoxicity	Drug/toxin exposure history
Hypokalemia ^[11]	Severe K⁺ depletion → cell membrane instability → muscle breakdown	Electrolyte panel
Malignant hyperthermia	Uncontrolled Ca²⁺ release from sarcoplasmic reticulum (RYR1 mutation) → sustained contraction → necrosis	Triggered by anaesthetic agents (halothane, isoflurane) ^[2]; perioperative setting

Key point: Rhabdomyolysis gives massively elevated CK and myoglobinuria — identical to severe IMNM. The distinction is that rhabdomyolysis is acute and has an identifiable trigger, whereas IMNM is subacute/chronic and progressive without an obvious precipitant (or persists after trigger removal).

Category	Condition	CK	Weakness Pattern	Key Distinguishing Feature
IIM	DM	Moderate ↑	Proximal, symmetric	Skin rash (heliotrope, Gottron's)
	PM	Moderate–high ↑	Proximal, symmetric	CD8+ T-cell infiltrate on biopsy
	IBM	Normal–mild ↑	Proximal + distal	Insidious onset, rimmed vacuoles, treatment-refractory
	Anti-synthetase	Moderate–high ↑	Proximal	ILD, mechanic's hands, arthritis, fever
	Overlap	Variable	Proximal	Features of underlying CTD
Drug-induced	Statin toxic	Mild–moderate ↑	Proximal	Resolves with statin cessation
	Steroid myopathy	Normal	Proximal	On steroids; no necrosis; CK normal
	Colchicine	Mild ↑	Proximal ± distal	Neuromyopathy; CKD
Endocrine	Hypothyroidism	Mild–moderate ↑	Proximal	TFT abnormal; delayed relaxation reflexes
	Cushing's	Normal	Proximal	Cushingoid features
	Hypokalemia	Variable (may ↑↑)	Proximal, episodic	Low K⁺; ECG changes
NMJ	Myasthenia gravis	Normal	Fatigable; ocular/bulbar	AChR Ab; decremental EMG
Genetic	Muscular dystrophy	High ↑	Proximal (LGMD)	Family history; young onset; genetic test
	Myotonic dystrophy	Mild ↑	Distal > proximal	Myotonia; family history; CTG repeat
Infectious	Viral myositis	Mild–moderate ↑	Diffuse	Acute, febrile, self-limiting
	Pyomyositis	Mild ↑	Focal	Focal abscess; fever
Other	MND/ALS	Mild ↑	UMN + LMN	Fasciculations; UMN signs
	Rhabdomyolysis	Very high ↑↑↑	Variable	Acute precipitant; resolves
	Paraneoplastic	Variable	Proximal	Occult malignancy on screening

When facing a patient with subacute proximal weakness + very high CK + no rash:

Exclude drug-induced → Stop statins/other offenders; if improves → toxic myopathy; if persists → consider IMNM
Exclude endocrine/metabolic → TFT, electrolytes (K⁺, Ca²⁺, PO₄), cortisol
Exclude infection → Viral serology, blood cultures if febrile
Check myositis-specific antibodies → anti-SRP, anti-HMGCR, anti-Jo1, anti-Mi2, anti-MDA5
EMG → Myopathic pattern (rules out neuropathy, NMJ)
MRI muscles → Oedema pattern guides biopsy site
Muscle biopsy → The definitive test: necrosis + regeneration + minimal inflammation + MAC deposition = IMNM
Malignancy screen → CT TAP, tumour markers, NPC screen (EBV serology, nasopharyngoscopy in HK), age-appropriate cancer screening

High Yield Summary — Differential Diagnosis of IMNM

Closest mimics within IIM: DM (has skin rash), PM (CD8+ T-cell infiltrate), IBM (distal weakness, insidious, refractory), anti-synthetase (ILD, mechanic's hands)
Drug-induced: Statin toxic myopathy (resolves with cessation) vs anti-HMGCR+ IMNM (persists); steroid myopathy (normal CK — the ironic trap)
Endocrine: Hypothyroidism (check TFT), Cushing's, hypokalemia (check K⁺)
NMJ: Myasthenia gravis — fatigable weakness, ocular involvement, normal CK
Genetic: LGMD and myotonic dystrophy — family history, genetic testing
Infectious: Viral myositis — acute, febrile, self-limiting
Malignancy: Must screen in ALL IIM patients, especially seronegative IMNM; NPC in Hong Kong
Key distinguishing features of IMNM: Very high CK (> 10× ULN), NO rash, subacute progression, necrosis without inflammation on biopsy, anti-SRP or anti-HMGCR positive, does NOT resolve with statin cessation

Active Recall - Differential Diagnosis of IMNM

References

^[1] Senior notes: Maksim Medicine Notes.pdf (Rheumatology — Idiopathic inflammatory myopathies, p.318) ^[2] Senior notes: Ryan Ho Neurology.pdf (10.4.3 Inflammatory Myopathies, p.194) ^[3] Senior notes: Ryan Ho Rheumatology.pdf (Autoantibody-defined subsets table and malignancy association, p.91–92) ^[4] Lecture slides: Block A - Rheumatology Interactive Tutorial.pdf (Case 2 — IIM subtypes, learning objectives) ^[5] Senior notes: Adrian Lui Pediatrics Notes.pdf (Myotonic Dystrophy and Inflammatory Myopathies, p.145) ^[6] Senior notes: learning_points_output.txt (Neurology — Two Cases of Lower Limb Weakness, Learning Point 1) ^[7] Lecture slides: Neurology- Two cases of lower limb weakness.pdf (Differential Diagnosis of Myopathy table, p.38) ^[8] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Differential diagnosis of IIM, p.1757) ^[9] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (Differential diagnosis of myopathies table, p.706) ^[10] Senior notes: Ryan Ho Rheumatology.pdf (Diagnosis section — autoantibodies, p.92) ^[11] Senior notes: Block A - Electrolyte and Acid-Base Disorders.pdf (Hypokalemia complications, p.27)

Diagnostic Criteria, Diagnostic Algorithm, and Investigations for Autoimmune Necrotizing Myopathy

1. Diagnostic Criteria

Diagnosing IMNM is not a single-test exercise. It requires integrating clinical findings, serology, electrophysiology, imaging, and — critically — muscle biopsy. Let's walk through the relevant criteria frameworks.

These were originally designed for PM and DM, not IMNM (which wasn't recognised as a separate entity until the 2000s). However, they remain the foundation upon which modern criteria are built:

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

1. Symmetrical weakness of limb-girdle muscles and anterior neck flexors 2. Muscle biopsy: typical of myositis 3. Muscle enzyme elevation (esp. CK) 4. EMG: typical of myositis (spontaneous fibrillation; polyphasic low-amplitude motor unit potential) 5. Cutaneous manifestations of DM: e.g. heliotrope rash, Gottron's papules ^[1]

Limitation for IMNM: These criteria were designed before IMNM was recognised. IMNM patients satisfy criteria 1, 3, and 4, but their biopsy pattern (necrosis without significant inflammation) doesn't fit the "typical myositis" expected in criterion 2 under the original framework. This led to years of IMNM being misclassified as PM.

2017 EULAR/ACR classification criteria for IIM: include age of onset, antibodies (only anti-Jo1 now), different scoring with / without muscle biopsy ^[1]

This is a probability-based scoring system using a decision tree and weighted variables:

Variable	Score (without biopsy)	Score (with biopsy)
Age of onset ≥18 years vs ≥40 years	1.3 / 2.1	1.5 / 1.5
Muscle weakness: proximal UL	0.7	0.7
Muscle weakness: proximal LL	0.5	0.8
Dysphagia / oesophageal dysmotility	0.7	0.6
Anti-Jo1 positive	3.9	3.9
↑CK or ↑LDH or ↑AST/ALT	1.3	1.4
Muscle biopsy: endomysial infiltration of mononuclear cells surrounding but not invading myofibres	N/A	1.7
Muscle biopsy: perifascicular atrophy	N/A	1.9
Muscle biopsy: rimmed vacuoles	N/A	3.1
Skin features (heliotrope, Gottron's, Gottron's sign)	3.1–3.7	3.1–3.7

A probability score ≥ 55% without biopsy or ≥ 90% with biopsy classifies a patient as having IIM.

Relevance to IMNM: The 2017 criteria classify someone as having IIM in general, but do not specifically sub-classify IMNM. Sub-classification into IMNM requires the additional step of autoantibody profiling + characteristic biopsy findings.

These are the most specific diagnostic criteria for IMNM and remain the standard used in clinical practice:

Criterion	Requirement
Clinical	Subacute or acute onset of proximal, symmetric muscle weakness
Muscle enzymes	Markedly elevated CK (typically > 10× ULN, often > 50× ULN)
EMG	Myopathic pattern (no neuropathic features)
Muscle biopsy (essential)	Prominent myofibre necrosis with myophagocytosis (macrophages engulfing dead fibres) + regenerating fibres + sparse or absent lymphocytic inflammatory infiltrate + no perifascicular atrophy
Additional biopsy features	MAC (C5b-9) deposition on sarcolemma of non-necrotic fibres; MHC class I upregulation on non-necrotic fibres; capillary C5b-9 deposition (anti-SRP+); pipestem capillaries (anti-SRP+)
Autoantibodies	Anti-SRP and/or anti-HMGCR (present in ~60–80% of cases; ~20–30% are seronegative)
Exclusion	Must exclude other IIM subtypes (DM by absence of rash/perifascicular atrophy; PM by absence of endomysial CD8+ T-cell invasion; IBM by absence of rimmed vacuoles); must exclude non-autoimmune causes (drug toxicity that resolves, endocrine, genetic)

High Yield — Biopsy Is the Gold Standard for IMNM

Unlike DM where characteristic skin findings may suffice clinically, IMNM requires muscle biopsy for definitive diagnosis. The biopsy pattern of necrosis + regeneration + minimal inflammation + MAC deposition is what definitively separates IMNM from PM (CD8+ T cells invading fibres), DM (perifascicular atrophy), and IBM (rimmed vacuoles). Without biopsy, you can suspect IMNM (very high CK + positive anti-SRP/HMGCR + no rash), but you cannot confirm it.

Here is a comprehensive step-by-step algorithm integrating the clinical approach, investigations, and criteria:

High Yield — GC Interactive Tutorial Investigation Sequence

The GC rheumatology interactive tutorial case demonstrates the investigation approach in sequence ^[4]:

CK 1570 U/L (NR 22–198) — elevated muscle enzymes
ANA positive with a titre of 1/160 — marker of autoimmunity
Myositis specific antibody test reported as positive for anti-Jo1 antibody — identifies subtype
EMG shows low amplitude motor-units potentials with occasional fibrillation potentials, compatible with inflammatory myopathy — confirms myopathic process
PFT shows reduced FVC 70% predicted and DLCO 64% predicted — assesses respiratory muscle and parenchymal involvement
HRCT reveals ground glass opacities predominantly over the lower lobes. No honeycombing — characterises ILD

This same systematic sequence applies to investigating IMNM, though the antibody profile and biopsy findings will differ.

3. Investigation Modalities — Detailed Breakdown

3A. Blood Investigations

Enzyme	Rationale	Expected Findings in IMNM	Interpretation Notes
Creatine kinase (CK)	Released from damaged muscle membrane ^[12]^[13]; most sensitive and specific marker of muscle damage	Usually > 10× ULN, may even be > 50–100× ULN in severe cases ^[10]; often 5,000–50,000+ U/L	CK values: rarely normal (~5%) ^[10]. If CK is normal, seriously reconsider the diagnosis
LDH	Cytoplasmic enzyme released from damaged cells (less specific — also from RBCs, liver, heart)	Elevated	Non-specific; contributes to the enzyme profile
AST / ALT	Released from damaged muscle as well as liver	Elevated (may be mistaken for liver disease!)	Always check CK alongside AST/ALT — if CK is very high and AST/ALT mildly elevated, the "transaminitis" is likely from muscle, not liver
Aldolase	Enzyme in glycolytic pathway; released from muscle	Elevated	Less commonly measured but can be elevated when CK is borderline

CK values in context ^[12]^[13]:

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

In IMNM, CK commonly exceeds 10,000 IU/L — this is a distinguishing feature

AST/ALT Trap

A common clinical error: an elevated AST/ALT in a patient with IMNM is reflexively attributed to liver disease, triggering unnecessary hepatology investigations. Always check CK first. If CK is markedly elevated, the "liver enzymes" are almost certainly of muscular origin. AST and ALT are present in skeletal muscle and leak out during necrosis, just like CK.

Marker	Expected in IMNM	Notes
ESR	Often mildly to moderately elevated	Non-specific; can be elevated in any inflammatory/autoimmune process
CRP	Often mildly to moderately elevated	↑↑ESR/CRP ^[10] — general markers of inflammation

Investigation	Purpose	What You're Looking For
CBC ^[10]	Baseline; exclude haematological malignancy	Usually normal; anaemia of chronic disease possible
RFT ^[10]	Renal function — rhabdomyolysis can cause AKI	↑Creatinine, ↑urea if myoglobin-induced AKI
LFT ^[10]	Distinguish muscle-origin transaminases from true liver disease	GGT and bilirubin should be NORMAL if the transaminitis is from muscle
TFT ^[10]^[12]^[13]	R/o thyroid myopathy ^[10] — hypothyroidism can mimic inflammatory myopathy	↑TSH, ↓fT4 → hypothyroid myopathy
Electrolytes ^[12]^[13]	Exclude hypokalemia, hypocalcaemia, hypophosphataemia	Any of these can cause myopathy and even rhabdomyolysis
Urinalysis	Myoglobinuria	Dipstick positive for "blood" but no RBCs on microscopy → myoglobin!

This is where the diagnostic precision for IMNM lies. The autoantibody profile sub-classifies the IIM and predicts prognosis and treatment response.

High Yield — GC Lecture: Autoantibodies in IIM

The significance of a positive anti-nuclear antibodies test ^[4]

Diagnostic role of the various autoantibodies in autoimmune rheumatic disease ^[4]

This is explicitly listed as a GC learning objective.

a) Myositis-Specific Antibodies (MSAs) — Only found in myositis

Antibody	Associated IIM Subtype	Clinical Significance
Anti-SRP	IMNM	Severe myopathy with muscle fibre necrosis / endomysial fibrosis with minimal inflammatory infiltrates; aggressive disease refractory to high-dose steroids and immunosuppressants ^[3]
Anti-HMGCR	IMNM	Statin-associated autoimmune myopathy; persists after statin cessation; ~30–40% are statin-naïve
Anti-Jo1	Anti-synthetase syndrome	Mechanic's hands, ILD, Raynaud's, non-erosive arthritis, fever ^[3]; most common anti-synthetase antibody; included in 2017 EULAR/ACR criteria ^[1]
Anti-Mi2	DM (classic)	Good prognosis, responds well to therapy ^[3]
Anti-MDA5	CADM	Cutaneous ulceration, erythematous painful palmar macules/papules, alopecia, oral ulcers ^[3]; associated with rapidly progressive ILD
Anti-TIF1γ	DM (cancer-associated)	Strongest cancer association in adult DM
Anti-NXP2	DM	Confers a higher risk of malignancy ^[14]
Anti-SAE	DM	Initially amyopathic, then develops myositis

b) Myositis-Associated Antibodies (MAAs) — Found in other CTDs too

Antibody	Associated CTD	Notes
Anti-Ro/SSA, Anti-La/SSB	Sjögren's, SLE	Found in other autoimmune rheumatic diseases associated with myositis ^[14]
Anti-Sm	SLE	Generally negative in JDM and JPM ^[14]
Anti-U1 RNP	MCTD	Overlap myositis
Anti-PM/Scl	SSc-myositis overlap	Identify a small, distinct subgroup of myopathies with a protracted disease course often complicated by pulmonary interstitial fibrosis and/or cardiac involvement ^[14]

c) ANA

An anti-nuclear antibodies test is reported as positive with a titre of 1/160 ^[4].

ANA is positive in ~60–80% of IIM patients overall
In IMNM specifically, ANA may be negative (especially anti-HMGCR+ cases) — ANA negativity does NOT exclude IMNM
A positive ANA is non-specific and must be interpreted in context

3B. Electrophysiology

Purpose: To r/o neuropathic disorders ^[10] — the primary role of EMG is to confirm the process is myopathic, not neuropathic.

Myositis: defined as 2 out of 3 of: ↑muscle enzymes, EMG typical of myositis, Muscle biopsy ^[10].

EMG Finding	Significance	Pathophysiology
Spontaneous fibrillation potentials at rest ^[1]^[10]	Indicates muscle membrane instability → denervated or necrotic fibres firing spontaneously	In IMNM, necrotic fibres lose sarcolemma integrity → uncontrolled depolarisation
Polyphasic or short-duration potentials on voluntary contraction ^[1]^[10]	= Myopathic motor unit potentials → fewer functioning fibres per motor unit; the surviving fibres produce smaller, fragmented signals	In IMNM, many fibres in each motor unit are necrotic → the motor unit potential becomes smaller and polyphasic because fewer fibres contribute synchronously
Salvos of repetitive potentials on mechanical stimulation of nerve ^[10] (complex repetitive discharges)	Groups of fibres fire in synchronized bursts	Reflects irritability of regenerating fibres
Low amplitude motor-units potentials with occasional fibrillation potentials, compatible with inflammatory myopathy ^[4]	Consolidates the myopathic pattern	From the GC tutorial case
Normal nerve conduction velocities	Rules out neuropathy	Motor and sensory nerve conduction should be normal in a pure myopathic process

EMG Pattern: Myopathic vs Neuropathic

Feature	Myopathic (IMNM, DM, PM)	Neuropathic (GBS, CIDP, MND)
Motor unit potentials	Small, short, polyphasic	Large, long, polyphasic
Spontaneous activity	Fibrillations, positive sharp waves	Fibrillations, fasciculations
Recruitment	Early recruitment (many small units fire early)	Reduced recruitment (few large units fire)
NCS	Normal	Abnormal (↓velocity in demyelinating; ↓amplitude in axonal)

Why early recruitment in myopathy? Because individual motor units are weakened (fewer functioning fibres), the CNS compensates by activating MORE motor units earlier to generate force. In neuropathy, entire motor units are lost, so fewer units are available → reduced recruitment.

Typically normal unless severe muscle necrosis and atrophy are present ^[14]
Purpose: rule out concurrent neuropathy (important in colchicine-induced neuromyopathy, diabetic neuropathy, etc.)
If NCS is abnormal → reconsider the diagnosis or look for overlap with neuropathic conditions

3C. Imaging

MRI: sensitive but non-specific ^[10].

Sequence	Finding in Active IMNM	Interpretation
T2-weighted / STIR	Patchy ↑T2W indicating inflammation, oedema ^[10]; diffuse bilateral symmetrical signal hyperintensity in proximal muscles (thighs, upper arms)	Active muscle oedema/necrosis → increased water content → bright on T2/STIR
T1-weighted	Fatty replacement (hyperintense streaks within muscle)	Chronic damage → irreversible fatty infiltration replacing necrotic muscle. If present, indicates delayed diagnosis
Post-gadolinium T1	Enhancement of actively inflamed/necrotic areas	Helps distinguish active from chronic disease

Why MRI?

Guides biopsy site ^[10] — you want to biopsy muscle that is oedematous (active disease) but NOT completely replaced by fat (end-stage, unhelpful)
Assesses extent and distribution of disease
Monitors treatment response — resolving oedema indicates improving disease
D/dx: muscular dystrophy, metabolic, rhabdomyolysis ^[10] — helps refine the differential

Distribution pattern in IMNM: Tends to affect posterior thigh compartment (hamstrings > quadriceps) and medial compartment more than lateral. This differs from IBM (which preferentially affects quadriceps and forearm flexors).

Modality	Purpose	Findings to Look For
CXR	Baseline screen for ILD	Faint reticulation over bilateral lower zones ^[4]
HRCT thorax	Gold standard for ILD characterisation	Ground glass opacities predominantly over the lower lobes. No honeycombing ^[4] → suggests NSIP pattern (non-specific interstitial pneumonia), which is the most common ILD pattern in IIM

Investigations of interstitial lung disease ^[4] — explicitly a GC learning objective.

ILD is less common in pure IMNM compared to anti-synthetase syndrome or DM with anti-MDA5, but must be screened for because it affects management and prognosis.

PFT shows a reduced forced vital capacity of 70% predicted and diffusion capacity of the lungs for carbon monoxide of 64% predicted ^[4].

Parameter	What It Measures	Expected Finding	Interpretation
FVC	Lung volumes (restrictive pattern?)	↓ in ILD or respiratory muscle weakness	If FVC is ↓ but DLCO is normal → likely respiratory muscle weakness. If BOTH are ↓ → ILD
DLCO	Gas exchange efficiency across alveolar membrane	↓ in ILD (parenchymal damage reduces diffusion surface area)	↓DLCO out of proportion to ↓FVC → suggests parenchymal disease (ILD), not just weak muscles
MIP/MEP (maximal inspiratory/expiratory pressures)	Respiratory muscle strength directly	↓ in IMNM if diaphragm/intercostal weakness	Helps distinguish "can't breathe because muscles are weak" from "can't breathe because lungs are diseased"

3E. Muscle Biopsy — The Definitive Investigation

Muscle Bx: at muscle that is most affected ^[12]^[13]. Done on weak but not atrophied muscle → guided by P/E, EMG ± MRI ^[10].

Open biopsy (traditional) or needle biopsy (less invasive, but smaller sample)
Site selection: Choose a muscle that is clinically weak (reduced MRC grade) but NOT severely atrophied or replaced by fat
- Commonly biopsied muscles: deltoid or quadriceps (vastus lateralis)
- Avoid the muscle used for EMG on that side (needle trauma causes artefactual inflammation)
- MRI guidance optimises yield — biopsy the area showing T2/STIR hyperintensity

Finding	Description	Pathophysiological Explanation
Myofibre necrosis	Pale, eosinophilic fibres with loss of cross-striation; may show hyaline degeneration	MAC-mediated sarcolemma rupture → cell death; cytoplasm becomes homogeneous as proteins denature
Myophagocytosis	Macrophages surrounding and engulfing dead fibres	Macrophages are recruited to clear necrotic debris — this is clean-up, NOT the primary attack
Regenerating fibres	Basophilic, small calibre, centrally placed nuclei	Satellite cells (muscle stem cells) activate → proliferate → fuse into new myotubes; basophilia from abundant ribosomal RNA
Minimal lymphocytic infiltration	Sparse T cells (if any); NO endomysial CD8+ T-cell invasion of non-necrotic fibres	This is what distinguishes IMNM from PM — the attack is humoral (antibody/complement), not cell-mediated
MAC (C5b-9) deposition on sarcolemma	Immunohistochemistry shows C5b-9 deposits on the surface of non-necrotic fibres	Complement activation has occurred → MAC assembles on sarcolemma → next step would be pore formation and necrosis. Catching it on non-necrotic fibres shows the "attack in progress"
MHC class I upregulation	Diffuse sarcolemmal MHC-I expression on non-necrotic fibres	Normal muscle does NOT express MHC-I. Upregulation indicates immune activation — the fibres are presenting antigens and are under immune attack
Pipestem capillaries (anti-SRP+)	Thickened capillary walls with hyalinisation	Complement-mediated endothelial damage in small vessels
No perifascicular atrophy	Atrophy is NOT preferentially at fascicle edges	Perifascicular atrophy is the hallmark of DM (ischaemia from perimysial vasculopathy); its ABSENCE helps exclude DM
No rimmed vacuoles	No autophagic vacuoles with eosinophilic rim	Rimmed vacuoles are the hallmark of IBM; their ABSENCE helps exclude IBM

High Yield — Biopsy Pattern Comparison Across IIMs

Feature	IMNM	DM	PM	IBM
Dominant pathology	Necrosis + regeneration	Perifascicular atrophy	CD8+ T-cell invasion	Rimmed vacuoles + inclusions
Inflammatory infiltrate	Macrophage-dominant, sparse	Perivascular/perimysial B + CD4+ T cells	Endomysial CD8+ T cells	Endomysial CD8+ T cells + degenerative changes
MAC deposition	On sarcolemma of non-necrotic fibres (characteristic)	On capillaries (capillary damage)	Absent or minimal	Absent
MHC-I expression	Diffuse	Perifascicular	Diffuse	Diffuse
Perifascicular atrophy	Absent	Present — hallmark	Absent	Absent

Investigation	Purpose	Expected Findings in IMNM
ECG	Screen for arrhythmias, conduction defects	Sinus tachycardia, ST/T changes (if myocarditis), conduction blocks
Echocardiography	Screen for ventricular dysfunction, myocarditis	↓Ejection fraction, regional wall motion abnormalities (especially in anti-SRP+ IMNM)
Cardiac MRI	If echo abnormal — characterise myocardial inflammation/fibrosis	Late gadolinium enhancement (fibrosis/scar); T2 oedema (active myocarditis)
Troponin	Marker of myocardial injury	May be elevated from skeletal muscle (cross-reactivity) OR true cardiac involvement — interpret with echo

ECG/echo: detect cardiac muscle involvement ^[12]^[13]. Cardiac assessment is essential because anti-SRP+ IMNM in particular can cause clinically significant myocarditis and cardiomyopathy.

Potential association between cancer and dermatomyositis and the rationale of cancer screening ^[4]. Thorough malignancy screen in elderly ^[10].

Investigation	Target Malignancy	HK-Specific Relevance
CT TAP (chest/abdomen/pelvis)	Solid organ malignancies (lung, ovarian, gastric, pancreatic)	Standard baseline screen
EBV serology (VCA-IgA, EA-IgA)	NPC	NPC (this locality) ^[2] — high prevalence in Southern Chinese; must screen
Nasopharyngoscopy	NPC	Direct visualisation of nasopharynx
Mammography	Breast cancer	All female patients
Pap smear / HPV	Cervical cancer	All female patients of appropriate age
Colonoscopy	Colorectal cancer	Age-appropriate (> 50 years)
PSA	Prostate cancer	Male patients > 50 years
PET-CT	Occult malignancy	Consider if initial screen negative but high clinical suspicion (seronegative, older patient, constitutional symptoms)

1/3 malignancy (lung, breast, gastric, NPC) – usually diagnosed within 1 year of DM/PM ^[1]. Repeat screening should be considered at 3–6 month intervals for the first 3 years, especially in seronegative IMNM and in older patients.

She has mild to moderate dysphagia upon speech therapist assessment ^[4].

Bedside swallowing assessment by speech therapist
Video fluoroscopic swallowing study (VFSS) if aspiration is suspected
Identifies bulbar involvement and guides whether PO intake is safe vs need for NG/PEG feeding

Step	Investigation	Key Findings for IMNM
1	CK + muscle enzymes	Very high (> 10× ULN)
2	Baseline bloods (CBC, RFT, LFT, TFT, electrolytes)	Exclude metabolic/endocrine mimics
3	Myositis-specific antibodies	Anti-SRP or anti-HMGCR positive
4	EMG	Myopathic pattern; fibrillations
5	MRI muscles	T2/STIR hyperintensity (oedema); guides biopsy
6	Muscle biopsy	Necrosis + regeneration + minimal inflammation + MAC deposition
7	HRCT + PFT	Screen for ILD
8	ECG + Echo	Screen for cardiac involvement
9	Malignancy screen	CT TAP, EBV/NPC screen, age-appropriate
10	Swallowing assessment	If dysphagia present

High Yield Summary — Diagnosis of IMNM

No single diagnostic test — diagnosis requires integration of clinical, serological, electrophysiological, and histopathological data
Bohan and Peter criteria (1975): PM requires all 4 clinical criteria; DM requires 3 + skin ^[1] — historical but still examined
2017 EULAR/ACR criteria: Probability-based scoring for IIM overall; does NOT sub-classify IMNM
ENMC criteria for IMNM: Requires biopsy showing necrosis + regeneration + minimal inflammation ± MAC deposition; anti-SRP or anti-HMGCR; exclusion of other causes
CK: Usually > 10× ULN — rarely normal (~5%) ^[10]; highest among all IIM subtypes
Autoantibodies: Anti-SRP (severe, refractory) and anti-HMGCR (statin-associated) are IMNM-specific
EMG: Myopathic pattern — short, polyphasic MUPs + fibrillation potentials ^[1]^[10]
MRI: T2/STIR hyperintensity guides biopsy; T1 fatty replacement indicates chronicity
Muscle biopsy: Gold standard — necrosis, regeneration, macrophage predominance, sparse lymphocytes, MAC on sarcolemma, no perifascicular atrophy, no rimmed vacuoles
Always screen for malignancy — especially NPC in HK — and for ILD and cardiac involvement

Active Recall - Diagnosis of IMNM

References

^[1] Senior notes: Maksim Medicine Notes.pdf (Rheumatology — Idiopathic inflammatory myopathies, Diagnostic criteria, p.318) ^[2] Senior notes: Ryan Ho Neurology.pdf (10.4.3 Inflammatory Myopathies, p.194) ^[3] Senior notes: Ryan Ho Rheumatology.pdf (Autoantibody-defined subsets table, p.91) ^[4] Lecture slides: GC_Interactive tutorial (Rheum case 2) student copy.pdf (Learning objectives and Case P2 investigations); Senior notes: Block A - Rheumatology Interactive Tutorial.pdf (Case 2) ^[10] Senior notes: Ryan Ho Rheumatology.pdf (Diagnosis section — myositis criteria, autoantibodies, management, p.92) ^[12] Senior notes: Ryan Ho Neurology.pdf (10.4 Diseases of Muscles — Investigations, p.191) ^[13] Senior notes: Adrian Lui Pediatrics Notes.pdf (Inflammatory Myopathies — Investigations, p.143–145) ^[14] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (Serum autoantibodies and EMG, p.709)

Management of Autoimmune Necrotizing Myopathy

Before diving into specific drugs, let's establish why we treat IMNM the way we do. The management logic flows directly from the pathophysiology:

Pathophysiological Target	Therapeutic Strategy	Rationale
Autoantibody production (anti-SRP, anti-HMGCR)	Deplete B cells (rituximab); reduce antibody titres (plasmapheresis, IVIG)	Antibodies are the primary effectors → removing them interrupts the attack
Complement activation → MAC deposition	High-dose steroids suppress complement cascade; IVIG scavenges complement	MAC formation is the terminal step causing sarcolemma rupture
Ongoing autoimmune stimulation	Steroid-sparing immunosuppressants (AZA, MTX, MMF, CYC)	Long-term immune suppression prevents recurrent cycles of necrosis
Persistent antigen exposure (HMGCR on regenerating fibres)	Stop the offending statin (necessary but NOT sufficient)	Removing the initial trigger, but the autoimmune loop is already self-sustaining
Muscle damage → functional impairment	Physiotherapy, rehabilitation	Preserve function, prevent contractures, promote recovery
Bulbar involvement → aspiration risk	Speech therapy, modified diet, PEG tube	Protect the airway
Malignancy driving the immune process	Treat the underlying malignancy	In paraneoplastic IMNM, treating the cancer may lead to myositis improvement

Key Principle — IMNM Is Antibody-Mediated

Unlike PM/DM where steroids alone may suffice, IMNM is driven by autoantibodies and complement — a humoral mechanism. This is why IMNM often requires earlier and more aggressive use of B-cell–targeted therapies (rituximab, IVIG) compared to other IIMs. Anti-SRP: aggressive disease refractory to high-dose steroids and immunosuppressants ^[3] — knowing this changes your management escalation timeline.

3. Treatment Modalities — Detailed Breakdown

3A. Step 0: Immediate Measures

Mandatory in all suspected anti-HMGCR+ IMNM
Rationale: while stopping the statin alone will NOT cure established IMNM (the autoimmune cycle is self-perpetuating), continued statin use provides ongoing antigen stimulus → perpetuates the disease
The patient should never be re-challenged with any statin (class effect — all HMG-CoA reductase inhibitors carry the risk)
For cardiovascular risk management, switch to alternative lipid-lowering agents: ezetimibe (cholesterol absorption inhibitor — different mechanism, no HMGCR upregulation), PCSK9 inhibitors (evolocumab, alirocumab), or fibrates if needed

Severity Marker	Mild–Moderate	Severe / Life-Threatening
MRC power grade	4/5 proximally	≤ 3/5 proximally; cannot walk; bedbound
CK	5–10× ULN	> 50× ULN
Swallowing	Intact or mild dysphagia	Severe dysphagia, choking, aspiration risk
Respiratory	FVC > 80% predicted	FVC < 50% predicted; resp distress
Cardiac	Normal echo/ECG	↓EF, arrhythmia, myocarditis
Rhabdomyolysis	No AKI	Myoglobinuria, rising creatinine, AKI

Severe disease: Initiate IV methylprednisolone pulse + consider IVIG simultaneously + early rituximab
Mild-moderate disease: Oral prednisolone + steroid-sparing agent may suffice initially

Search for and treat any malignancy ^[10]

If a malignancy is identified, treating the cancer is a critical component of management — in paraneoplastic IMNM, immunosuppression alone without addressing the tumour may be ineffective
Temporal relationship: can be diagnosed before, with or after diagnosis of inflammatory myopathy ^[2]

Before starting immunosuppression, screen for:

Screen	Rationale
HBV serology (HBsAg, anti-HBs, anti-HBc)	Reactivation risk with rituximab and other immunosuppressants; start antiviral prophylaxis (entecavir) if HBsAg+ or anti-HBc+
HCV serology	Treatment of underlying HCV if present
TB screening (CXR + IGRA/Mantoux)	Risk of TB reactivation with steroids/immunosuppression; start isoniazid prophylaxis if latent TB
Bone density (DEXA)	Baseline before long-term steroid use
TPMT genotype (if planning azathioprine)	Thiopurine methyltransferase deficiency → risk of severe myelosuppression with azathioprine
Baseline CBC, RFT, LFT	Monitor for drug toxicity

High dose steroids ^[10] — this is the universal first-line for all IIMs.

Regimen	Dose	Duration	Indication
Oral prednisolone	1 mg/kg/day (max 60–80 mg/day)	Start high, then taper after 4–8 weeks of improvement	Standard induction for mild–moderate IMNM
IV methylprednisolone pulse	500–1000 mg/day for 3–5 days	Followed by oral prednisolone taper	Severe disease: bedbound, respiratory compromise, severe dysphagia, rhabdomyolysis with AKI

How steroids work in IMNM (from first principles):

Glucocorticoids bind the intracellular glucocorticoid receptor → translocate to nucleus → suppress transcription of pro-inflammatory cytokines (IL-1, IL-6, TNF-α)
Reduce B-cell activity → decrease autoantibody production
Suppress complement activation
Stabilise lysosomal membranes → reduce tissue damage
In IMNM, steroids provide the initial rapid immunosuppression to break the cycle of necrosis, but they are rarely sufficient alone (especially in anti-SRP+ disease)

Steroid taper: After clinical improvement (improving power, falling CK), taper gradually:

Reduce by 10 mg/week from 60 mg → 40 mg
Then by 5 mg/week from 40 mg → 20 mg
Then by 2.5 mg/month from 20 mg → 5–10 mg maintenance (or off)
Total taper duration: typically 6–12 months
CK and clinical power guide the taper — if CK rises or power drops during taper, slow down or reverse

Steroid Myopathy vs Disease Relapse — The Management Dilemma

A patient on steroids whose weakness worsens may have either disease relapse (increase immunosuppression) or steroid myopathy (reduce steroids). The critical discriminator: check the CK. In disease relapse, CK rises. In steroid myopathy, CK is normal (because the mechanism is atrophy, not necrosis). This single blood test determines whether you turn the steroid dose up or down — a life-or-death distinction.

Side effects of chronic steroids and prophylaxis:

Side Effect	Mechanism	Prophylaxis
Osteoporosis	↓Osteoblast activity, ↑osteoclast activity	Calcium + Vitamin D supplementation; bisphosphonate if duration > 3 months
Glucose intolerance / DM	↑Hepatic gluconeogenesis, ↓peripheral insulin sensitivity	Monitor blood glucose; start hypoglycaemics if needed
Gastric ulcer	↓Prostaglandin synthesis → ↓mucosal protection	PPI co-prescription (especially if concomitant NSAIDs)
Immunosuppression → infection	Suppression of cell-mediated and humoral immunity	Vaccinations (before rituximab); PJP prophylaxis (co-trimoxazole) if high-dose steroids
Adrenal suppression	Exogenous steroid suppresses HPA axis	Do NOT stop steroids abruptly; taper slowly
Cushing's features	Redistribution of fat, protein catabolism	Minimize dose and duration; steroid-sparing agents
Cataracts, glaucoma	Direct lens/aqueous humour effects	Ophthalmology review
AVN of femoral head	↓Blood supply to bone (mechanism unclear, possibly fat emboli or vasculitis)	Clinical monitoring; MRI if hip pain

Started concurrently with or within 2–4 weeks of steroids. The rationale: allow steroid dose reduction while maintaining immunosuppression. These agents take weeks to months to reach full efficacy (they are "slow-acting"), so starting them early is essential.

High dose steroids + immunosuppressants, e.g. azathioprine, MTX, cyclophosphamide ^[10]

Agent	Mechanism	Dose	Onset	Key Monitoring	Contraindications/Cautions
Azathioprine (AZA)	Purine analogue → inhibits DNA synthesis → suppresses lymphocyte proliferation (both T and B cells)	2–3 mg/kg/day PO	3–6 months to full effect	FBC (myelosuppression), LFT (hepatotoxicity); check TPMT genotype first (deficiency → fatal pancytopenia)	TPMT deficiency; concomitant allopurinol (inhibits xanthine oxidase → ↑active metabolite → toxicity)
Methotrexate (MTX)	Folate antagonist → inhibits dihydrofolate reductase → blocks DNA/RNA synthesis in rapidly dividing immune cells	7.5–25 mg/week PO/SC + folic acid supplementation	4–8 weeks	FBC, LFT, RFT; CXR at baseline (MTX lung)	Renal impairment (renally excreted → accumulates); pregnancy (teratogenic); active infection; liver disease; MTX lung → hypersensitivity reaction
Mycophenolate mofetil (MMF)	Inhibits inosine monophosphate dehydrogenase → blocks de novo purine synthesis → selective lymphocyte suppression (lymphocytes rely on de novo pathway, unlike other cells which can use salvage pathway)	1–1.5 g BD PO	2–3 months	FBC (cytopenias), LFT, GI symptoms (diarrhoea, nausea)	Pregnancy (teratogenic); concomitant azathioprine (overlapping mechanism → excessive myelosuppression)
Cyclophosphamide (CYC)	Alkylating agent → cross-links DNA → cytotoxic to rapidly dividing cells (especially B cells)	IV pulse: 0.5–1 g/m² monthly for 3–6 months; or PO 1–2 mg/kg/day	2–4 weeks (faster than AZA/MTX)	FBC (leucopenia nadir at 10–14 days), urinalysis (haemorrhagic cystitis), LFT	Haemorrhagic cystitis (co-administer MESNA for IV pulse to neutralise acrolein); infertility (gonadotoxic); malignancy risk (↑bladder cancer with cumulative dose); avoid in young women if possible
Tacrolimus	Calcineurin inhibitor → blocks IL-2 transcription → suppresses T-cell activation	0.05–0.1 mg/kg/day PO; target trough 5–10 ng/mL	2–4 weeks	Drug trough levels, RFT (nephrotoxic), glucose (diabetogenic), BP (hypertension), Mg²⁺ (hypomagnesaemia)	Renal impairment; uncontrolled hypertension; concomitant nephrotoxic drugs

Why Mycophenolate Is Increasingly Favoured Over Azathioprine

MMF selectively suppresses lymphocytes because they are uniquely dependent on the de novo purine synthesis pathway (which MMF blocks). Other cell types can use the salvage pathway and are relatively spared. This gives MMF a better side-effect profile than AZA (less bone marrow toxicity overall). However, AZA remains widely used because it is cheaper and has more long-term safety data.

Which agent to choose?

AZA or MMF: First-line for most IMNM patients; good safety profiles for long-term use
MTX: Good option, especially if there is concurrent arthritis (anti-inflammatory AND immunosuppressive); avoid if significant renal impairment or ILD (MTX can cause pneumonitis — confusing the picture)
CYC: Reserved for severe, rapidly progressive, or refractory disease due to toxicity profile; sometimes used as induction for very aggressive anti-SRP+ IMNM
Tacrolimus: Used in some Asian centres with good results in IMNM; may be particularly useful in anti-SRP+ disease refractory to first-line agents

3D. Step 3: Escalation for Refractory Disease

If the patient does not respond to steroids + one conventional immunosuppressant within 4–8 weeks (CK not falling, power not improving, or worsening):

IVIG for refractory disease ^[10]

Parameter	Detail
Dose	2 g/kg total dose, divided over 2–5 days
Frequency	Can be repeated monthly for 3–6 months, then tapered
Mechanism	Multi-pronged: (a) Anti-idiotypic antibodies neutralise pathogenic autoantibodies; (b) Fc receptor blockade on macrophages → reduced phagocytosis of antibody-coated fibres; (c) Complement scavenging → binds and inactivates C3b/C4b → blocks MAC formation; (d) Modulates cytokine networks; (e) Accelerates catabolism of pathogenic IgG via FcRn saturation
Why it works in IMNM	Because IMNM is antibody and complement mediated, IVIG directly counteracts BOTH effector mechanisms. This makes it particularly effective in IMNM compared to PM (which is T-cell mediated)
Key advantages	Rapid onset of action (days); well-tolerated; can be used as bridge therapy while waiting for immunosuppressants to take effect
Side effects	Headache, fever, chills (infusion reactions); aseptic meningitis; thromboembolic events (IVIG increases blood viscosity); renal failure (osmotic nephrosis, especially with sucrose-containing preparations)
Contraindications	IgA deficiency (risk of anaphylaxis from anti-IgA antibodies in the preparation); severe renal impairment
Monitoring	RFT before and after; hydration; slow infusion rate initially

Anti-CD20 (still experimental) ^[10] — note: this was listed as experimental in the senior notes from ~2018–2020. By 2025–2026, rituximab is now considered standard of care for refractory IMNM based on accumulating evidence.

Parameter	Detail
Dose	1 g IV × 2 doses, 2 weeks apart (RA-protocol); or 375 mg/m² × 4 weekly doses (lymphoma-protocol)
Repeat cycles	Typically every 6 months based on clinical response and B-cell counts
Mechanism	Rituximab is a chimeric monoclonal antibody against CD20, a surface marker expressed on pre-B cells and mature B cells (but NOT on plasma cells or pro-B cells). Binding CD20 → antibody-dependent cellular cytotoxicity (ADCC) + complement-dependent cytotoxicity → B-cell depletion → reduced autoantibody production over subsequent weeks-months
Why it works in IMNM	IMNM is driven by autoantibodies produced by B cells. Depleting the B-cell precursors that differentiate into antibody-secreting plasma cells eventually reduces autoantibody titres. The effect is not immediate (existing long-lived plasma cells are NOT depleted by rituximab — they lack CD20), which is why combination with IVIG (for immediate antibody neutralisation) is logical
Key advantages	Highly effective in antibody-mediated diseases; durable responses (months); now well-established safety profile
Side effects	Infusion reactions (pre-medicate with paracetamol + antihistamine + methylprednisolone); ↑infection risk (especially bacterial, viral reactivation — HBV!); progressive multifocal leukoencephalopathy (PML — very rare, JC virus); hypogammaglobulinaemia with repeated cycles
Contraindications	Active severe infection; HBV without antiviral cover (risk of fulminant reactivation); severe hypogammaglobulinaemia
Pre-treatment	HBV serology mandatory; start entecavir prophylaxis if HBsAg+ or anti-HBc+; vaccinations (especially pneumococcal and influenza) should be given ≥2 weeks BEFORE rituximab (B-cell depletion renders vaccines ineffective)

Why Rituximab Does Not Work Immediately

Rituximab depletes B cells, but long-lived plasma cells in the bone marrow do NOT express CD20 and are NOT depleted. These plasma cells continue producing autoantibodies for weeks to months even after B-cell depletion. This is why rituximab takes 2–4 months for clinical effect, and why bridging therapy with IVIG (which provides immediate antibody neutralisation and complement scavenging) is used in the interim.

3E. Step 4: Strategies for Persistent Refractory Disease

If the patient remains refractory after steroids + steroid-sparing agent + IVIG + rituximab:

Parameter	Detail
Mechanism	Physical removal of circulating autoantibodies and complement components from the plasma
Protocol	Typically 5–7 exchanges over 10–14 days
Indication	Acute, severe IMNM with life-threatening features (severe rhabdomyolysis + AKI, respiratory failure, severe dysphagia with aspiration); bridge therapy
Limitation	Effect is temporary — antibodies are regenerated within days to weeks unless concurrent immunosuppression is given. Must be combined with definitive therapy
Side effects	Hypotension (from volume shifts), hypocalcaemia (citrate anticoagulant chelates calcium), infection (removal of protective immunoglobulins), coagulopathy (removal of clotting factors)

If AZA failed → try MMF or tacrolimus
If MTX failed → try CYC
Some case series report benefit with combination therapy (e.g., rituximab + MMF + low-dose steroids + monthly IVIG)

If the patient is truly refractory to all the above:

Is the diagnosis correct? — Could this be IBM (which does NOT respond to immunosuppression), a muscular dystrophy, or a metabolic myopathy?
Is there an occult malignancy driving the disease that has been missed?
Is steroid myopathy contributing to the weakness (CK normal but weakness worsening on steroids)?
Repeat muscle biopsy may be warranted to reassess the pathology

Supportive (for late bulbar S/S): PT, speech therapy, PEG tube ^[10]

Supportive Measure	Indication	Rationale
Physiotherapy (PT) ^[10]	All patients	Maintains muscle strength, prevents contractures, promotes recovery of regenerating fibres; aerobic exercise improves cardiovascular fitness and fatigue; resistance exercise safe in stable/improving disease
Speech therapy ^[10]	Dysphagia, dysphonia	Swallowing exercises, safe swallowing techniques, modified diet consistency to reduce aspiration risk
PEG tube (percutaneous endoscopic gastrostomy) ^[10]	Severe, persistent dysphagia with aspiration risk; inability to maintain adequate nutrition PO	Provides enteral nutrition while bypassing the oropharyngeal stage of swallowing; prevents aspiration pneumonia
Respiratory support	Respiratory muscle weakness (↓FVC)	Non-invasive ventilation (NIV/BiPAP) for nocturnal hypoventilation; monitor FVC serially; ICU if FVC < 1L or acute respiratory failure
Occupational therapy	Functional impairment in ADLs	Assistive devices, home modifications, energy conservation techniques
Psychological support	Chronic illness, functional disability	Depression and anxiety are common; address early
Vasodilators for Raynaud's ^[10]	If overlap with Raynaud's phenomenon	Calcium channel blockers (nifedipine); keep hands warm; avoid cold exposure

3G. Disease-Specific Considerations

Stop statin permanently — the single most important first step
Many anti-HMGCR+ patients respond reasonably well to steroids + one immunosuppressant (AZA or MMF)
Add IVIG or rituximab if refractory
Statin-naïve anti-HMGCR+ patients may have more aggressive disease requiring earlier escalation
Lipid management: Switch to ezetimibe ± PCSK9 inhibitors; monitor cardiovascular risk closely

Anti-SRP: severe myopathy with muscle fibre necrosis / endomysial fibrosis with minimal inflammatory infiltrates on histology. Aggressive disease refractory to high-dose steroids and immunosuppressants ^[3]

Anticipate refractoriness — do NOT wait 8 weeks on steroids alone before escalating
Start steroids + immunosuppressant AND consider early IVIG + rituximab from the outset
Cardiac screening is especially important (higher risk of myocarditis)
Some experts advocate CYC induction for severe anti-SRP+ IMNM

Highest malignancy association — thorough and repeated cancer screening essential
Treatment generally follows the same algorithm (steroids + immunosuppressant ± IVIG/rituximab)
If a malignancy is found, treating the cancer may improve the myositis

Parameter	Frequency	Target
CK	Every 2–4 weeks during induction; every 1–3 months during maintenance	Normalisation or near-normalisation; CK should fall BEFORE power improves
Muscle power (MRC grading)	Every clinic visit	Progressive improvement; full recovery takes months
Autoantibody titres (anti-SRP/HMGCR)	Every 3–6 months	Falling titres correlate with response; rising titres may herald relapse
CBC, RFT, LFT	Every 2–4 weeks initially (for drug toxicity); monthly once stable	Detect myelosuppression (AZA, MTX, CYC), hepatotoxicity (MTX, AZA), nephrotoxicity (CYC, tacrolimus)
FVC	Serial if respiratory involvement	Improvement or stability; decline indicates worsening respiratory muscle weakness or ILD
Echo/ECG	Baseline + repeat if cardiac symptoms	Monitor for cardiomyopathy (anti-SRP+)
Malignancy re-screening	Annually for at least 3 years	New malignancy can emerge
Bone density (DEXA)	Baseline + annually if on long-term steroids	Osteoporosis prevention

Step	Treatment	Indication	Onset of Action
0	Stop statins; severity assessment; malignancy screen; pre-treatment screen	All patients	Immediate
1	High-dose prednisolone (± IV methyl-pred pulse)	All patients — induction	Days–weeks
2	Steroid-sparing agent (AZA / MTX / MMF)	All patients — started concurrently or early	Weeks–months
3a	IVIG	Refractory; severe; as bridge therapy	Days
3b	Rituximab	Refractory; antibody-mediated; now standard of care	Weeks–months
4	Plasmapheresis; switch immunosuppressant; CYC; combination therapy	Persistent refractory disease	Days (PLEX); weeks (agents)
Ongoing	PT, speech therapy, PEG, respiratory support, steroid prophylaxis	All patients as needed	Continuous

High Yield — GC Lecture / Senior Notes Management Framework

Management of myositis ^[10]:

High dose steroids + immunosuppressants, e.g. azathioprine, MTX, cyclophosphamide
IVIG for refractory disease
Anti-CD20 (still experimental) — note: now standard of care in 2025/2026 for refractory IMNM
Supportive (for late bulbar S/S): PT, speech therapy, PEG tube
Lung fibrosis: high dose steroids + immunosuppressants
Search for and treat any malignancy
Prognosis: variable depending on type of myositis, severity, delay in dx and autoAb
Response to steroid: in general, overlap myositis > DM > PM ^[10] — IMNM (especially anti-SRP+) is at the refractory end of this spectrum

High Yield Summary — Management of IMNM

Stop statins permanently in anti-HMGCR+ IMNM (necessary but NOT sufficient — autoimmune cycle persists)
Induction: High-dose steroids (prednisolone 1 mg/kg/day or IV methylprednisolone pulse if severe)
Steroid-sparing agent: Start early — AZA, MTX, or MMF first-line; CYC or tacrolimus second-line
Escalation for refractory disease: IVIG (2 g/kg, rapid onset, bridges to rituximab); Rituximab (anti-CD20, depletes B cells, reduces autoantibody production — now standard of care, not "experimental")
Anti-SRP+ IMNM: Anticipate refractoriness — escalate early; consider IVIG + rituximab from outset
Steroid myopathy vs relapse: Check CK — normal CK = steroid myopathy (reduce steroids); rising CK = relapse (increase immunosuppression)
Supportive care: PT, speech therapy, PEG tube, respiratory monitoring, steroid prophylaxis (Ca/VitD, bisphosphonates, PPI, PJP prophylaxis)
Malignancy: Screen and treat; may improve paraneoplastic myositis
Monitoring: CK (falls before power improves), power, drug toxicity, autoantibody titres, cancer re-screening

Active Recall - Management of IMNM

References

^[2] Senior notes: Ryan Ho Neurology.pdf (10.4.3 Inflammatory Myopathies, p.194) ^[3] Senior notes: Ryan Ho Rheumatology.pdf (Autoantibody-defined subsets table — anti-SRP, p.91) ^[10] Senior notes: Ryan Ho Rheumatology.pdf (Management section — myositis treatment, prognosis, p.92)

Complications of Autoimmune Necrotizing Myopathy

The complications of IMNM arise from two broad sources: (A) the disease itself — direct consequences of ongoing autoimmune myofibre destruction and systemic immune activation — and (B) the treatment — side effects of the aggressive immunosuppression required to control the disease. Let's work through each systematically.

Two distinct mechanisms can cause respiratory compromise in IMNM, and distinguishing them is clinically critical because the treatments differ:

Mechanism	Pathophysiology	Clinical Features	Key Investigation
Respiratory muscle weakness	Autoimmune necrosis of the diaphragm and intercostal muscles → reduced ability to generate negative intrathoracic pressure → hypoventilation → CO₂ retention and hypoxia	Orthopnoea (diaphragm most affected when supine), paradoxical abdominal breathing, morning headaches (CO₂ retention overnight), declining FVC	Serial FVC measurements (upright AND supine — > 20% drop supine indicates diaphragm weakness); MIP/MEP; ABG showing type II respiratory failure
Interstitial lung disease (ILD)	Autoimmune alveolitis → fibrosis of alveolar-capillary membrane → impaired gas exchange	Progressive exertional dyspnoea, dry cough, bibasal fine inspiratory crackles	PFT: reduced FVC + reduced DLCO ^[4]; HRCT: ground glass opacities (active) ± honeycombing (fibrotic) ^[4]

She has mild to moderate dysphagia upon speech therapist assessment… PFT shows a reduced forced vital capacity of 70% predicted and diffusion capacity of the lungs for carbon monoxide of 64% predicted… HRCT reveals ground glass opacities predominantly over the lower lobes. There was no honeycombing ^[4].

Why the distinction matters: Respiratory muscle weakness improves with immunosuppression + NIV support and can be fully reversible. ILD with established fibrosis (honeycombing) is irreversible, and the goal shifts to preventing progression. Ground glass opacities (active inflammation) may still respond to aggressive immunosuppression, whereas honeycombing does not.

ILD is less common in pure IMNM than in anti-synthetase syndrome or anti-MDA5+ DM, but it can occur — especially in overlap cases or anti-SRP+ IMNM. Always screen with PFT and HRCT.

Investigations of interstitial lung disease ^[4] — explicitly listed as a GC learning objective.

Respiratory Emergency — When to Escalate

If FVC falls below 1 litre or below 50% predicted, or if the patient has respiratory distress, they need ICU admission for monitoring and potential non-invasive ventilation (NIV/BiPAP) or even mechanical ventilation. Serial bedside FVC monitoring (like in GBS) is essential. Do NOT wait for an ABG to deteriorate before acting.

Difficulty in swallowing food with 2 episodes of choking in the past week ^[4]. Dysphagia, nasal regurgitation, aspiration, aspiration pneumonia ^[3].

Step	Pathophysiology	Clinical Consequence
Pharyngeal striated muscle weakness	Autoimmune necrosis of the pharyngeal and upper oesophageal striated muscles → impaired propulsion of the food bolus	Difficulty swallowing solids → progressing to liquids; choking on food; nasal regurgitation (food comes out through the nose because the nasopharyngeal seal is weak)
Loss of airway protection	Weak suprahyoid muscles → poor laryngeal elevation → poor epiglottic closure during swallowing	Aspiration — food/liquid enters the trachea and lungs
Aspiration pneumonia	Aspirated material + oral bacteria → infection of the lower respiratory tract	Fever, productive cough, new consolidation on CXR; typically right lower lobe (due to anatomy of the right main bronchus being more vertical)

Management: Speech therapist assessment (as in the GC case), modified diet consistency, PEG tube if severe and persistent, treat aspiration pneumonia with antibiotics (amoxicillin-clavulanate or piperacillin-tazobactam to cover oral anaerobes and Gram negatives).

This is one of the most dangerous acute complications of IMNM, particularly in severe anti-SRP+ disease:

Step	Pathophysiology
1. Massive myofibre necrosis	Antibody/complement-mediated sarcolemma rupture → CK often > 10,000–50,000 U/L
2. Myoglobin release	Myoglobin (oxygen-binding protein in muscle) floods the bloodstream; normally bound to haptoglobin but overwhelms binding capacity
3. Myoglobin filtered by kidneys	Free myoglobin is filtered into renal tubules
4. Tubular obstruction and toxicity	Myoglobin precipitates in acidic urine → forms casts that obstruct tubules; myoglobin's haem moiety generates reactive oxygen species → direct tubular epithelial cell injury
5. AKI	Oliguria → rising creatinine → uraemia; may require dialysis

Clinical clues: Dark "cola-coloured" urine; urine dipstick positive for "blood" but no RBCs on microscopy (the dipstick detects the haem group in myoglobin, not actual haemoglobin from RBCs).

Prevention and management:

Aggressive IV fluid resuscitation (target urine output > 200–300 mL/hr) to flush myoglobin through tubules
Urine alkalinisation (IV sodium bicarbonate) — myoglobin precipitates less in alkaline urine
Monitor for hyperkalaemia (K⁺ leaks from necrotic muscle) — may require urgent management (calcium gluconate, insulin-dextrose, salbutamol nebulisers, resonium, dialysis)
Monitor for hypocalcaemia (calcium deposits in damaged muscle) and later hypercalcaemia (released during recovery phase)
Dialysis if refractory AKI, life-threatening hyperkalaemia, or fluid overload

The heart is a muscle. In IMNM, particularly anti-SRP+ disease, the autoantibodies can target cardiac myocytes that express the same antigens (SRP is a ubiquitous ribonucleoprotein).

Complication	Mechanism	Clinical Consequence
Myocarditis	Antibody/complement-mediated damage to cardiac myocytes	Chest pain, dyspnoea, heart failure, arrhythmias; ↑troponin; new wall motion abnormalities on echo
Cardiomyopathy	Chronic subclinical myocardial damage → fibrosis → progressive ventricular dysfunction	Dilated cardiomyopathy; ↓ejection fraction; heart failure
Arrhythmias / conduction defects	Inflammation or fibrosis involving the conduction system	Sinus tachycardia, atrial fibrillation, heart block, ventricular tachycardia; risk of sudden cardiac death

Systemic involvement, eg. pulmonary fibrosis, arthralgia, Raynaud's phenomenon… ^[2] — cardiac involvement is part of the systemic autoimmune picture.

Monitoring: ECG + echocardiography at baseline and during follow-up. Cardiac MRI if clinical suspicion of myocarditis (late gadolinium enhancement = fibrosis; T2 oedema = active inflammation).

If IMNM is diagnosed late or remains poorly controlled, repeated cycles of necrosis → regeneration → necrosis eventually exhaust the muscle's regenerative capacity:

Stage	Pathology	Imaging	Clinical Consequence
Early (active)	Necrosis + regeneration; satellite cells still active	MRI: T2/STIR hyperintensity (oedema)	Weakness is potentially reversible with treatment
Late (chronic)	Regenerative capacity exhausted → fatty replacement + fibrosis	MRI: T1 hyperintensity (fat signal replaces muscle)	Wasting/contractures (ONLY if chronic) ^[2] — weakness becomes irreversible even with effective immunosuppression

This is why early, aggressive treatment is paramount. Once muscle is replaced by fat and fibrous tissue, no amount of immunosuppression will restore function.

Adult form a/w malignancy: 5× risk in dermatomyositis, 2× risk in polymyositis ^[2]. 1/3 malignancy (lung, breast, gastric, NPC) – usually diagnosed within 1 year of DM/PM ^[1].

Potential association between cancer and dermatomyositis and the rationale of cancer screening ^[4].

While the malignancy risk in IMNM overall is lower than in DM, seronegative IMNM has the highest cancer association among IMNM subtypes. This is both a complication and a co-morbidity:

The malignancy may cause the IMNM (paraneoplastic — the tumour expresses muscle antigens, triggering cross-reactive autoimmunity)
Temporal relationship: can be diagnosed before, with or after diagnosis of inflammatory myopathy ^[2]
In HK: NPC (this locality) ^[2] must always be screened
Cancer re-screening should be repeated annually for at least 3 years from diagnosis, as the malignancy may emerge after the myopathy

Patients with active IMNM are at increased risk of DVT and PE due to:

Immobility (bedbound from severe weakness)
Systemic inflammation (pro-thrombotic state — elevated inflammatory cytokines activate coagulation cascade)
Active malignancy (if paraneoplastic — Trousseau syndrome)

Prevention: Prophylactic LMWH (enoxaparin) for hospitalised patients with reduced mobility; graduated compression stockings; early mobilisation with physiotherapy.

Proximal weakness → unstable gait → high risk of falls
Compounded by steroid-induced osteoporosis (treatment complication — see below)
Falls with hip/vertebral fractures are a significant source of morbidity, especially in elderly patients

Chronic high-dose steroid use is almost inevitable in IMNM management. The side effects are extensive and must be actively prevented:

Complication	Mechanism	Prevention/Management
Osteoporosis → fractures	↓Osteoblast activity + ↑osteoclast activity → bone loss	Calcium + Vitamin D; bisphosphonates (alendronate) if > 3 months use; DEXA monitoring
Steroid-induced diabetes	↑Hepatic gluconeogenesis + ↓peripheral insulin sensitivity	Blood glucose monitoring; metformin or insulin if needed
Steroid myopathy	Type IIb fibre atrophy from protein catabolism	Monitor CK (normal in steroid myopathy) — key differentiator from disease relapse; minimise steroid dose
Immunosuppression → infections	↓Cell-mediated and humoral immunity	PJP prophylaxis (co-trimoxazole) if high dose; monitor for TB, fungal infections
Cushing's syndrome	Exogenous hypercortisolism	Moon face, central obesity, striae, buffalo hump, thin skin, easy bruising — minimise dose/duration
Peptic ulcer / GI bleeding	↓Prostaglandin-mediated mucosal protection	PPI prophylaxis
Adrenal suppression	Chronic exogenous steroids suppress HPA axis → adrenal atrophy	Never stop steroids abruptly; sick-day rules (stress dosing during illness/surgery)
AVN of femoral head	Disrupted blood supply to femoral head (mechanism debated: fat emboli vs microvascular thrombosis)	MRI if hip pain; orthopaedic referral
Cataracts / glaucoma	Posterior subcapsular cataracts; ↑intraocular pressure	Ophthalmology review annually
Psychiatric effects	Mood instability, insomnia, psychosis	Anticipate; consider psychiatry referral if severe

Agent	Key Complications	Mechanism	Monitoring
Azathioprine	Myelosuppression (leucopenia, pancytopenia); hepatotoxicity; ↑infection risk; nausea	Inhibits purine synthesis → affects all rapidly dividing cells; TPMT deficiency → cannot metabolise → toxic accumulation	FBC every 2 weeks initially → monthly; LFT; TPMT genotype before starting
Methotrexate	Myelosuppression; hepatotoxicity (steatohepatitis → cirrhosis with cumulative dose); pneumonitis (MTX lung); mucositis; teratogenicity	Folate antagonism → blocks DNA synthesis; idiosyncratic pulmonary hypersensitivity	FBC + LFT every 2–4 weeks; co-prescribe folic acid 5 mg weekly (reduces side effects without reducing efficacy); CXR if new cough/dyspnoea
Mycophenolate (MMF)	GI effects (diarrhoea, nausea — most common); cytopenias; ↑infection risk; teratogenicity	Inhibits inosine monophosphate dehydrogenase → blocks de novo purine synthesis in lymphocytes; GI effects from direct mucosal toxicity	FBC every 2 weeks initially; LFT
Cyclophosphamide	Haemorrhagic cystitis; myelosuppression; infertility; ↑risk of bladder cancer (cumulative); opportunistic infections	Acrolein metabolite is toxic to bladder urothelium; alkylates DNA of gonadal cells	FBC (nadir at 10–14 days); urinalysis; co-administer MESNA (binds acrolein in urine); encourage high fluid intake; sperm/egg banking in young patients
Tacrolimus	Nephrotoxicity (chronic tubulointerstitial nephritis); neurotoxicity (tremor, headache); hyperglycaemia; hypertension; hypomagnesaemia	Calcineurin inhibition → renal vasoconstriction → ↓GFR; direct pancreatic β-cell toxicity	Trough levels; RFT; glucose; Mg²⁺; BP

Complication	Mechanism	Prevention/Management
Infusion reactions	Cytokine release from lysed B cells (especially first dose)	Pre-medicate with paracetamol + antihistamine + IV methylprednisolone; slow initial infusion rate
HBV reactivation	B-cell depletion removes immune surveillance of latent HBV → viral rebound → fulminant hepatitis	Mandatory HBV screening pre-treatment; entecavir prophylaxis if HBsAg+ or anti-HBc+; continue for ≥12 months after last rituximab dose
Hypogammaglobulinaemia	Repeated B-cell depletion → reduced immunoglobulin production → acquired humoral immunodeficiency	Monitor IgG levels; if recurrent infections + low IgG → consider IVIG replacement
Progressive multifocal leukoencephalopathy (PML)	JC virus reactivation in immunosuppressed state → demyelinating CNS infection	Very rare but devastating; monitor for new neurological symptoms; MRI + CSF JC virus PCR if suspected
Increased infection risk	Humoral immune suppression → impaired opsonisation and bacterial clearance	Vaccinate before treatment (pneumococcal, influenza); low threshold for investigating febrile episodes

Complication	Mechanism
Headache / aseptic meningitis	Immune complex deposition in meninges; osmotic shift
Thromboembolic events (DVT, PE, stroke)	↑Blood viscosity from high protein load; procoagulant factors in preparation
Renal failure	Osmotic nephrosis (especially with sucrose-containing formulations); renal tubular injury
Anaphylaxis	IgE-mediated reaction, especially in IgA-deficient patients (anti-IgA antibodies react with IgA in the IVIG preparation)
Haemolysis	Anti-A/anti-B isoagglutinins in IVIG preparations → passive haemolysis in non-O blood group recipients

Prognosis: variable depending on type of myositis, severity, delay in dx and autoAb ^[10]. 5–10% mortality ^[15].

Factor	Better Prognosis	Worse Prognosis
Autoantibody	Anti-HMGCR (especially statin-associated)	Anti-SRP (aggressive, refractory) ^[3]
Timing of treatment	Early diagnosis and treatment	Delayed diagnosis → irreversible fatty replacement
CK at presentation	Moderate elevation	Very high (> 50× ULN) with rhabdomyolysis
Organ involvement	Isolated myopathy	Cardiac involvement, ILD, severe dysphagia
Malignancy	No associated malignancy	Paraneoplastic — prognosis tied to cancer outcome
Age	Younger	Older (more comorbidities, higher malignancy risk)

Response to steroid: in general, overlap myositis > DM > PM ^[10] — IMNM (especially anti-SRP+) is at the most refractory end of this spectrum. However, with modern combination therapy (steroids + immunosuppressant + IVIG + rituximab), many patients achieve good long-term outcomes.

High Yield Summary — Complications of IMNM

Disease-related:

Respiratory failure: From respiratory muscle weakness (reversible) OR ILD (may be irreversible if fibrotic) — always differentiate the two
Dysphagia → aspiration pneumonia: Pharyngeal/oesophageal striated muscle weakness; needs speech therapy assessment; PEG if severe
Rhabdomyolysis → AKI: Massive CK → myoglobinuria → tubular obstruction/toxicity; treat with IV fluids, alkalinisation, monitor K⁺/Ca²⁺; may need dialysis
Cardiac: Myocarditis, cardiomyopathy, arrhythmias — especially anti-SRP+; monitor with ECG/echo
Irreversible muscle damage: Fatty replacement/fibrosis if chronic and untreated — irreversible even with immunosuppression
Malignancy: Screen all patients; especially NPC in HK; seronegative IMNM has highest risk
VTE: Immobility + inflammation + possible occult malignancy
Falls/fractures: Weakness + steroid osteoporosis

Treatment-related:

Steroids: Osteoporosis, DM, steroid myopathy (normal CK!), infections, Cushing's, adrenal suppression, AVN, cataracts
Immunosuppressants: Myelosuppression, hepatotoxicity, infections, teratogenicity, haemorrhagic cystitis (CYC), nephrotoxicity (tacrolimus)
Rituximab: HBV reactivation (screen before!), hypogammaglobulinaemia, PML (rare), infusion reactions
IVIG: Thromboembolic events, renal failure, anaphylaxis (IgA deficiency), haemolysis

Active Recall - Complications of IMNM

References

High Yield Summary

Autoimmune Necrotizing Myopathy (IMNM) — Key Points:

Definition: Subtype of IIM characterised by myofibre necrosis with minimal inflammation on biopsy, distinct from PM/DM
Pathophysiology: Antibody + complement-mediated (humoral), NOT T-cell mediated → MAC deposition → sarcolemma rupture → massive CK elevation
Three subtypes by autoantibody: Anti-SRP+ (severe, refractory), Anti-HMGCR+ (statin-associated), Seronegative (highest malignancy risk)
Clinical features: Symmetric proximal weakness, very high CK (often > 10× ULN), NO skin rash, may have dysphagia and cardiac involvement
Statin association: Anti-HMGCR+ IMNM — statin upregulates HMGCR → neoantigen → autoimmune cycle that persists after statin withdrawal
Cancer screening essential: Especially NPC in Hong Kong; malignancy can occur before, with, or after onset ^[2]
Anti-SRP+: Aggressive disease refractory to high-dose steroids and immunosuppressants ^[3]
Distinguish from: DM (skin rash), PM (CD8+ T-cell infiltrate on biopsy), IBM (distal weakness, non-responsive, inclusion bodies), toxic statin myopathy (resolves with statin cessation)

High Yield Summary — Differential Diagnosis of IMNM

Closest mimics within IIM: DM (has skin rash), PM (CD8+ T-cell infiltrate), IBM (distal weakness, insidious, refractory), anti-synthetase (ILD, mechanic's hands)
Drug-induced: Statin toxic myopathy (resolves with cessation) vs anti-HMGCR+ IMNM (persists); steroid myopathy (normal CK — the ironic trap)
Endocrine: Hypothyroidism (check TFT), Cushing's, hypokalemia (check K⁺)
NMJ: Myasthenia gravis — fatigable weakness, ocular involvement, normal CK
Genetic: LGMD and myotonic dystrophy — family history, genetic testing
Infectious: Viral myositis — acute, febrile, self-limiting
Malignancy: Must screen in ALL IIM patients, especially seronegative IMNM; NPC in Hong Kong
Key distinguishing features of IMNM: Very high CK (> 10× ULN), NO rash, subacute progression, necrosis without inflammation on biopsy, anti-SRP or anti-HMGCR positive, does NOT resolve with statin cessation

High Yield Summary — Diagnosis of IMNM

No single diagnostic test — diagnosis requires integration of clinical, serological, electrophysiological, and histopathological data
Bohan and Peter criteria (1975): PM requires all 4 clinical criteria; DM requires 3 + skin ^[1] — historical but still examined
2017 EULAR/ACR criteria: Probability-based scoring for IIM overall; does NOT sub-classify IMNM
ENMC criteria for IMNM: Requires biopsy showing necrosis + regeneration + minimal inflammation ± MAC deposition; anti-SRP or anti-HMGCR; exclusion of other causes
CK: Usually > 10× ULN — rarely normal (~5%) ^[10]; highest among all IIM subtypes
Autoantibodies: Anti-SRP (severe, refractory) and anti-HMGCR (statin-associated) are IMNM-specific
EMG: Myopathic pattern — short, polyphasic MUPs + fibrillation potentials ^[1]^[10]
MRI: T2/STIR hyperintensity guides biopsy; T1 fatty replacement indicates chronicity
Muscle biopsy: Gold standard — necrosis, regeneration, macrophage predominance, sparse lymphocytes, MAC on sarcolemma, no perifascicular atrophy, no rimmed vacuoles
Always screen for malignancy — especially NPC in HK — and for ILD and cardiac involvement

High Yield Summary — Management of IMNM

Stop statins permanently in anti-HMGCR+ IMNM (necessary but NOT sufficient — autoimmune cycle persists)
Induction: High-dose steroids (prednisolone 1 mg/kg/day or IV methylprednisolone pulse if severe)
Steroid-sparing agent: Start early — AZA, MTX, or MMF first-line; CYC or tacrolimus second-line
Escalation for refractory disease: IVIG (2 g/kg, rapid onset, bridges to rituximab); Rituximab (anti-CD20, depletes B cells, reduces autoantibody production — now standard of care, not "experimental")
Anti-SRP+ IMNM: Anticipate refractoriness — escalate early; consider IVIG + rituximab from outset
Steroid myopathy vs relapse: Check CK — normal CK = steroid myopathy (reduce steroids); rising CK = relapse (increase immunosuppression)
Supportive care: PT, speech therapy, PEG tube, respiratory monitoring, steroid prophylaxis (Ca/VitD, bisphosphonates, PPI, PJP prophylaxis)
Malignancy: Screen and treat; may improve paraneoplastic myositis
Monitoring: CK (falls before power improves), power, drug toxicity, autoantibody titres, cancer re-screening

High Yield Summary — Complications of IMNM

Disease-related:

Respiratory failure: From respiratory muscle weakness (reversible) OR ILD (may be irreversible if fibrotic) — always differentiate the two
Dysphagia → aspiration pneumonia: Pharyngeal/oesophageal striated muscle weakness; needs speech therapy assessment; PEG if severe
Rhabdomyolysis → AKI: Massive CK → myoglobinuria → tubular obstruction/toxicity; treat with IV fluids, alkalinisation, monitor K⁺/Ca²⁺; may need dialysis
Cardiac: Myocarditis, cardiomyopathy, arrhythmias — especially anti-SRP+; monitor with ECG/echo
Irreversible muscle damage: Fatty replacement/fibrosis if chronic and untreated — irreversible even with immunosuppression
Malignancy: Screen all patients; especially NPC in HK; seronegative IMNM has highest risk
VTE: Immobility + inflammation + possible occult malignancy
Falls/fractures: Weakness + steroid osteoporosis

Treatment-related:

Steroids: Osteoporosis, DM, steroid myopathy (normal CK!), infections, Cushing's, adrenal suppression, AVN, cataracts
Immunosuppressants: Myelosuppression, hepatotoxicity, infections, teratogenicity, haemorrhagic cystitis (CYC), nephrotoxicity (tacrolimus)
Rituximab: HBV reactivation (screen before!), hypogammaglobulinaemia, PML (rare), infusion reactions
IVIG: Thromboembolic events, renal failure, anaphylaxis (IgA deficiency), haemolysis

Autoimmune Necrotizing Myopathy

1. Definition

2. Epidemiology

3. Anatomy and Function: The Skeletal Muscle

Muscle Architecture

Why Proximal Muscles Are Preferentially Affected

Muscle Enzymes

4. Aetiology and Pathophysiology

4.1 Aetiological Classification of IMNM

4.2 Pathophysiology — From First Principles

Step 1: Trigger and Loss of Tolerance

Step 2: Immune Effector Mechanisms

Step 3: Consequences of Chronic Muscle Damage

5. Classification

5.1 Within the IIM Family

5.2 IMNM Subtypes by Autoantibody

6. Clinical Features

6.1 Symptoms

6.2 Signs

6.3 Systemic Manifestations

7. Distinguishing IMNM from Other Causes of Proximal Weakness

Framework for Proximal Weakness

Key Distinguishing Features of IMNM vs Other IIMs

8. Clinical Approach to a Patient with Suspected IMNM

History Taking — Systematic Approach

Physical Examination — Systematic Approach

Active Recall - Autoimmune Necrotizing Myopathy

References

1. The Overarching Framework: Where Is the Lesion?

2. Differential Diagnosis of IMNM — Systematic Categorisation

2A. Other Idiopathic Inflammatory Myopathies (IIMs)

i. Dermatomyositis (DM)

ii. Polymyositis (PM)

iii. Inclusion Body Myositis (IBM)

iv. Anti-synthetase Syndrome

v. Overlap Myositis

2B. Drug-Induced Myopathy

i. Statin Toxic Myopathy (Non-Immune)

ii. Other Drug-Induced Myopathies

2C. Endocrine/Metabolic Myopathies

2D. Infectious Myositis

2E. Neuromuscular Junction Disorders

2F. Inherited/Genetic Myopathies

2G. Motor Neuron Disease (ALS / MND)

2H. Paraneoplastic Myopathy

2I. Rhabdomyolysis (Non-Autoimmune)

3. Summary Differential Diagnosis Table

4. A Practical Diagnostic Sieve for the Ward

Active Recall - Differential Diagnosis of IMNM

1. Diagnostic Criteria

1A. Classic Bohan and Peter Criteria (1975) — Historical Foundation

1B. 2017 EULAR/ACR Classification Criteria for IIM

1C. 2004 ENMC (European Neuromuscular Centre) Criteria for IMNM

2. Diagnostic Algorithm

3. Investigation Modalities — Detailed Breakdown

3A. Blood Investigations

i. Muscle Enzymes

ii. Inflammatory Markers

iii. Baseline Screening Bloods

iv. Autoantibodies

3B. Electrophysiology

i. Electromyography (EMG)

ii. Nerve Conduction Studies (NCS)

3C. Imaging

i. MRI of Skeletal Muscles

ii. Chest Imaging

3D. Pulmonary Function Tests (PFTs)

3E. Muscle Biopsy — The Definitive Investigation

Biopsy Technique

Histopathological Findings in IMNM

3F. Cardiac Assessment

3G. Malignancy Screening

3H. Swallowing Assessment

4. Summary: Investigative Approach to Suspected IMNM

Active Recall - Diagnosis of IMNM

1. Principles of Management — Thinking From First Principles

2. Management Algorithm

3. Treatment Modalities — Detailed Breakdown

3A. Step 0: Immediate Measures

i. Stop Statins