Inclusion body myositis (IBM) is probably the most common acquired muscle disease in adults older than 50 years. Clinically, it is characterized by rather selective, and usually asymmetric, quadriceps and long finger flexor weakness. Creatine kinase can range from normal to 10–15 times the normal value. Muscle biopsy is the gold standard for diagnosis and is known to have a high specificity though relatively low sensitivity.1 Serum autoantibodies against NT5c1-alpha IgG (cN1A) were discovered in 2012 and have been available for clinical diagnostic use in the recent years.2–4 Initial studies of these antibodies reported high specificity (>90%) and modest sensitivity (50%–70%). This has led to increased clinical utilization of this test in cases of suspected IBM, especially when the muscle biopsy does not meet all required criteria.2,3 In some cases, seropositivity for those antibodies was evident several years before clinical diagnosis of IBM.2 However, like most antibody tests, more frequent ordering leads to discovery of positive results with uncertain clinical correlation.5 Here, we describe 2 cases in which the cN1A antibody, tested by Western blot, was positive in diseases other than IBM.
CASE REPORT: PATIENT 1
A 68-year-old man had a history of diabetes mellitus and poliomyelitis in his early 20s. This resulted in quadriplegia without need for ventilatory support. He underwent a 6-month rehabilitation to regain his ability to stand and subsequently required lifelong bilateral ankle foot orthoses. He was referred to our clinic for sensory complaints—namely burning dysesthesias in both hands—and increasing weakness. He had a history of prior bilateral carpal tunnel release and ulnar nerve decompressions at the elbow. He reported at least one fall because of his new symptoms. Examination revealed clear atrophy of the left ventral forearm and bilateral quadriceps, left more than right. There was mild weakness of the left abductor pollicis brevis and finger extensors, and moderate to severe weakness of left long finger flexors and knee extensors. He also had bilateral weakness of foot dorsiflexors, less than antigravity. Reflexes were 2+ and symmetric except for ankle jerks, which were absent. Creatine kinase was normal. Magnetic resonance imaging of the cervical spine showed mild foraminal stenosis at C5–C6 but no clear structural pathology to explain his symptoms. Nerve conduction studies showed a mild left ulnar neuropathy at the elbow, a mild right median neuropathy at the wrist, and no evidence of sensory polyneuropathy. Needle electromyography examination showed reduced recruitment of very large, long-duration motor unit potentials without spontaneous activity, suggestive of chronic denervation with subsequent reinnervation. There was no electrodiagnostic evidence of a myopathy. Skin biopsy showed a mild reduction of epidermal nerve fiber density at the foot consistent with a small fiber neuropathy that was attributed to his long-standing diabetes. cN1A antibody testing was ordered specifically because of the severe and asymmetric weakness of long finger flexors and quadriceps muscles, raising concerns about IBM. It returned positive. A left quadriceps muscle biopsy was ordered, which showed marked fiber-type grouping, consistent with remote denervation and reinnervation of muscle, but no features of IBM: no rimmed vacuoles, amyloid aggregates, or inflammation (Fig. 1). Patient thus was diagnosed with post-polio syndrome and referred for ongoing physical therapy and pain management.
CASE REPORT: PATIENT 2
A 60-year-old previously healthy woman reported a 7-month history of progressive muscle weakness. She began experiencing bilateral lower extremity weakness while on vacation out of the country, noting difficulty raising on her toes and climbing stairs. There was no associated pain or sensory symptoms. She was unable to run within 2 months from symptom onset. At 3 months, she noted upper extremity weakness, and at 5 months, she was wheelchair dependent. She further developed dyspnea on exertion and unintentional weight loss of 25 lbs. Extensive evaluation completed at another institution included unremarkable cerebrospinal fluid routine studies, and magnetic resonance imaging of brain and entire spine: upon our own review, we noted some mild bilateral mild foraminal stenosis at C4–C5 and C5–C6 but no other structural abnormality or abnormal enhancement after contrast administration. Creatine kinase was mildly elevated (635 IU/L, normal is <200 IU/L). She had a left deltoid muscle biopsy before referral, showing atrophy of both type I and II fiber types, consistent with denervation. We did not identify any characteristic features of IBM. Serum cN1A antibodies, ordered by the referring neurologist for unclear reasons, were positive. She was prescribed intravenous immunoglobulin for 3 months without any benefit. At the time of our initial evaluation, examination showed tongue and mental fasciculations, lower facial weakness, a brisk jaw jerk, and combined upper motor neuron (marked hyperreflexia) and lower motor neuron (amyotrophy, fasciculations) signs in the cervical and lumbar regions. An electromyography showed widespread denervation without any motor conduction block. Overall, the findings were consistent with El Escorial clinically definite, rapidly progressive amyotrophic lateral sclerosis. The patient died 8 months after the onset of her disease. At the time of her demise, there was nothing to support a diagnosis of IBM besides a positive CN1A antibody.
Serum cN1A antibodies were initially reported to have high specificity (>90%) and only modest sensitivity (50%–70%) for the diagnosis of IBM. The availability of the test through commercial laboratories in the past 5 years has led to increasing use in clinical practice. In our study, antibodies were detected by Western blot assay (Washington University in St Louis), and positive results were confirmed by enzyme-linked immunosorbent assay, as previously described.6 Positive results are known to occasionally occur in other inflammatory myopathies such as dermatomyositis and polymyositis, and the autoimmune conditions systemic lupus erythematosus and Sjogren syndrome.3,7 In one study, 5% of healthy volunteers were also found to have cN1A antibodies.7
In 2017, the first 2 cases of positive serology in patients with underlying motor neuron disease were described.5 The mechanism by which these antibodies are produced in motor neuron disease remains unclear. The antigenic target of the antibody is a muscle-specific 5′ nucleotidase that catalyzes the hydrolytic conversion of the purine adenosine monophosphate to adenosine.3,4 Imbalance of purinergic pathways has been implicated in the pathogenesis of amyotrophic lateral sclerosis.8 Our 2 additional cases highlight the importance of careful clinical, electrophysiologic, and histopathologic correlations to confirm or refute a suspected diagnosis of IBM. We also stress the risk of misdiagnosis by overreliance on positive cN1A serologies, especially when such aforementioned correlations are deferred. Further large-scale studies to evaluate the specificity of cN1A antibodies by testing individuals with neuromuscular diagnoses that mimic IBM are worthwhile.
1. Lloyd TE, Mammen AL, Amato AA, et al. Evaluation and construction of diagnostic criteria for inclusion body myositis
. Neurology. 2014;83:426–433.
2. Benjamin Larman H, Salajegheh M, Nazareno R, et al. Cytosolic 5′-nucleotidase 1A autoimmunity in sporadic inclusion body myositis
. Ann Neurol. 2013;73:408–418.
3. Herbert MK, Stammen-Vogelzangs J, Verbeek MM, et al. Disease specificity of autoantibodies to cytosolic 5′-nucleotidase 1A in sporadic inclusion body myositis
versus known autoimmune diseases. Ann Rheum Dis. 2016;75:696–701.
4. Pluk H, van Hoeve BJA, van Dooren SHJ, et al. Autoantibodies to cytosolic 5′-nucleotidase 1A in inclusion body myositis
. Ann Neurol. 2013;73:397–407.
5. Liewluck T. Anti-cytosolic 5’-nucleotidase 1A (cN1A) autoantibodies in motor neuron diseases. Neurology. 2017;89:2017–2018.
6. Goyal NA, Cash TM, Alam U, et al. Seropositivity for NT5c1A antibody in sporadic inclusion body myositis
predicts more severe motor, bulbar and respiratory involvement. J Neurol Neurosurg Psychiatry. 2016;87:373–378.
7. Lloyd TE, Christopher-Stine L, Pinal-Fernandez I, et al. Cytosolic 5′-nucleotidase 1A as a target of circulating autoantibodies in autoimmune diseases. Arthritis Care Res (Hoboken). 2016;68:66–71.
8. Volonté C, Apolloni S, Parisi C, et al. Purinergic contribution to amyotrophic lateral sclerosis
. Neuropharmacology. 2016;104:180–193.