What are the possible causes of myopathy with normal creatine kinase and negative inflammatory markers?

Causes of Myopathy with Normal CK and Negative Inflammatory Markers

The differential diagnosis for myopathy with normal creatine kinase and negative inflammatory markers includes muscular dystrophies (particularly late-onset limb-girdle and dysferlinopathies), mitochondrial myopathies, endocrine myopathies (thyroid disorders, hyperparathyroidism), drug-induced myopathies, metabolic myopathies, and certain inflammatory myopathies—particularly dermatomyositis and immune-mediated necrotizing myopathy. 1

Inflammatory Myopathies Despite Normal CK

While elevated CK is typical in inflammatory myopathies, several important exceptions exist:

Dermatomyositis with Normal CK

• Dermatomyositis can present with normal CK levels and represents a poor prognostic sign, often associated with malignancy or severe interstitial lung disease 2
• One-year survival in dermatomyositis patients with normal CK was only 33% in one series 2
• These patients may show perimysial pathology, less frequent cutaneous involvement, fewer fibrillation potentials on EMG, but higher erythrocyte sedimentation rates compared to dermatomyositis with elevated CK 3
• Anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis can present with severe inflammatory myopathy on biopsy despite normal CK 4

Immune-Mediated Necrotizing Myopathy (IMNM)

• Anti-SRP antibody-associated necrotizing myopathy typically presents with acute onset, dilated cardiomyopathy, and poor response to standard immunosuppression 1
• While IMNM usually shows markedly elevated CK (often >10 times normal), some cases may present with less dramatic elevations 5
• Statin-induced myopathy can demonstrate biopsy-confirmed myopathy with mitochondrial dysfunction (abnormal lipid stores, absent cytochrome oxidase activity, ragged red fibers) despite persistently normal CK levels 6

Polymyositis with Normal CK

• Adult idiopathic polymyositis can fulfill definite diagnostic criteria despite normal CK levels 7
• This presentation does not necessarily indicate poor prognosis when lung disease or malignancy are absent 7

Non-Inflammatory Myopathies

Muscular Dystrophies

• Late-onset muscular dystrophy, limb-girdle dystrophy (dysferlinopathies), adult-onset nemaline myopathy with monoclonal gammopathy, and myotonic dystrophy type 2 should be considered 1
• Muscle biopsy shows reduction or absence of dystrophin, degenerating/regenerating fibers, and replacement with fat or connective tissue 1
• Genetic testing for the dystrophin gene is indicated 1

Mitochondrial Myopathies

• Classic histopathologic findings include subsarcolemmal and interfibrillar mitochondrial accumulation on Gomori trichrome stain, "ragged red fibers," and reduction/absence of cytochrome c oxidase 1
• These can present with proximal weakness and may have normal or only mildly elevated CK 1

Endocrine Myopathies

• Thyroid disorders and hyperparathyroidism commonly cause myopathy with normal or minimally elevated CK 1
• These are reversible with treatment of the underlying endocrine disorder 1

Drug-Induced Myopathy

• Beyond statins, multiple medications can cause myopathy with variable CK elevation 1
• Corticosteroid-induced myopathy typically presents with normal CK 1

Overlap Syndromes

Myasthenia Gravis with Inflammatory Myopathy

• IIM overlapping with myasthenia gravis can present with mild CK elevation (mean ~888 U/L), dyspnea without interstitial lung disease, and anti-acetylcholine receptor antibody positivity 8
• These patients are typically negative for myositis-specific antibodies but show CD3+ T cell infiltration on muscle biopsy 8
• Inflammatory myopathy complicating myasthenia gravis can occur with normal CK throughout the clinical course, with only myoglobin elevation 9

Diagnostic Approach

Essential Testing

• EMG should be performed to confirm myopathic process (polyphasic motor unit action potentials of short duration and low amplitude with increased insertional activity, fibrillation potentials, sharp waves) and to target muscle for biopsy 1
• Muscle biopsy remains the gold standard for differentiating inflammatory from non-inflammatory myopathy and is critical when CK is normal 1
• Choose a weak muscle demonstrated by EMG abnormalities; biopsy the contralateral side 1

Additional Laboratory Testing

• Check aldolase levels, as selective aldolase elevation with normal CK occurs in dermatomyositis, immune-mediated myopathy with perimysial pathology, and overlap myositis 3
• Myositis-specific antibodies (anti-Jo-1, anti-SRP, anti-HMGCR, anti-Mi2, anti-MDA5) help define subgroups and prognosis 1
• Thyroid function tests and parathyroid hormone to exclude endocrine causes 1
• Consider genetic testing for muscular dystrophy when biopsy suggests this diagnosis 1

Imaging

• MRI with T2-weighted and STIR sequences can identify muscle edema and inflammation, guide biopsy site, and monitor treatment response even when CK is normal 1
• T1-weighted images show muscle atrophy and chronic damage 1

Critical Clinical Pitfalls

• Do not exclude inflammatory myopathy based solely on normal CK, particularly in dermatomyositis where this finding portends worse prognosis and higher malignancy risk 2
• Normal CK in polymyalgia-like syndromes helps differentiate from true myositis 1
• In patients on immune checkpoint inhibitors, polymyalgia-like syndrome presents with pain but not weakness, normal CK, and highly elevated inflammatory markers, distinguishing it from checkpoint inhibitor-induced myositis 1
• Cancer screening is essential in dermatomyositis with normal CK given the strong association with malignancy 1, 2