Challenge Case Report: Progressive Muscle Weakness

Case Resolution

VM was diagnosed with an immune-mediated necrotizing myopathy and started on prednisone 60 mg daily and methotrexate 10 mg weekly as well as folic acid 1 mg daily. Despite treatment, 1 month later, VM’s CK level increased to 3055 U/L. Thus, methotrexate was increased to 12.5 mg weekly, and IVIg was initiated at 2 g/kg monthly for 3 months. Three months later, the CK level had normalized, ranging from 65 to 114 U/L. The IVIg dose was decreased to 1 g/kg monthly, methotrexate was increased to 20 mg weekly, and prednisone was slowly weaned down to 2.5 mg daily. VM’s strength is now normal and VM is ambulating independently up to several miles. Treatment is being transitioned from IVIg 1 g/kg monthly to weekly subcutaneous immunoglobulin with a plan to wean steroids completely and continue maintenance therapy with subcutaneous immunoglobulin and methotrexate.

Discussion

Necrotizing myopathy and inflammatory myopathies (such as dermatomyositis, antisynthetase syndrome, and inclusion body myositis) have distinct pathologic characteristics. Whereas inflammatory myopathies with primary endomysial inflammation are characterized by otherwise healthy-appearing myofibers being surrounded and invaded by lymphocytes, necrotizing myopathy is characterized by degeneration, necrosis, and myophagocytosis without primary endomysial inflammation.¹

This is a clinically important distinction because inflammatory myopathies with primary endomysial inflammation can include antisynthetase syndromes and inclusion body myositis. In contrast, the differential diagnosis for necrotizing myopathies includes noninflammatory etiologies (such as toxic myopathy, rhabdomyolysis, or trauma) or inflammatory etiologies (such as HMGCR-associated myopathy, SRP-positive myopathy, or, in seronegative cases, immune-mediated necrotizing myopathy, which are often associated with cancers). The usual clinical approach to acquired necrotizing myopathies starts with a search for precipitating drugs or toxic agents; if these are absent, autoimmune mechanisms should be suspected.² In this case, MHC-I staining was helpful in distinguishing between noninflammatory and autoimmune etiologies, resulting in timely efficacious treatment.

The presence of abnormally increased sarcolemmal and sarcoplasmic MHC-I staining on nonnecrotic fibers helps differentiate between noninflammatory and inflammatory necrotizing myopathies. This has been well-characterized in idiopathic inflammatory myopathies and less so in necrotizing myopathies.^3,4 Without demonstration of MHC-I upregulation, it is difficult to distinguish between a toxic myopathy (which prompts a search for precipitating exposure) and an immune-mediated necrotizing myopathy (which prompts initiation of immunomodulating therapy).

There are 2 main caveats. First, necrotic fibers have increased expression of MHC-I, so the utility of MHC-I as a marker of autoimmunity lies in its upregulation on nonnecrotic fibers.⁵ Second, MHC-I upregulation is nonspecific, and may be seen in inflammatory muscular dystrophies (such as dysferlinopathies), which may mimic slowly progressive necrotizing myopathies but are not responsive to immunosuppression.⁶

In this case, the presence of MHC-I stain strengthens the diagnosis of an immune-mediated necrotizing myopathy. When the patient’s CK continued to increase despite a month of corticosteroid treatment, we were confident in escalating immunomodulatory therapy rather than evaluating for an alternative diagnosis. Thus, the MHC-I stain is an important histopathologic tool in directing accurate diagnosis and successful treatment of necrotizing myopathies.

Other immunohistochemical stains have supportive roles in the evaluation of inflammatory myopathies: most notably, membrane attack complex (C5b9). Abnormal deposition of C5b9 in capillary walls may be associated with “pipestem capillaries” and denote dermatomyositis as a microvasculopathy.⁷ In addition, sarcolemmal deposition of C5b9 can be prominent in immune-mediated necrotizing myopathy specimens, particularly those with SRP autoantibodies. C5b9 is not specific to microvasculitis or dermatomyositis.^8,9 Compared with MHC-I sarcolemmal staining, which is always detectable, C5b9 sarcolemmal staining can sometimes be absent.¹⁰

Another biomarker demonstrated to have increased sensitivity for dermatomyositis is myxovirus resistance protein 1 (MxA). MxA was developed as a pathologic diagnostic tool for dermatomyositis with improved sensitivity (71%) and preserved specificity (98%) compared with the gold standard pathologic hallmark of perifascicular atrophy (sensitivity 47%, specificity 98%).¹¹ Indeed, MxA overexpression and perifascicular atrophy were the 2 definitive pathologic criteria for dermatomyositis classification by the 2018 ENMC-DM. Out of 26 MxA-positive muscle specimens, 24 were dermatomyositis; the other 2 were immune-mediated necrotizing myopathy and antisynthetase syndrome.¹¹ In our patient, given the low positive TIF1-gamma, MxA staining would have been helpful in pathologic diagnosis of dermatomyositis vs other types of inflammatory myopathy. However, MxA is not yet widely available at all neuromuscular pathology laboratories and was not available at our testing center.

TIF1-y is a myositis-specific autoantibody most commonly associated with dermatomyositis and increased risk of malignancy.^12,13 Testing for myositis-specific and myositis-associated antibodies is available through commercial laboratories, such as LabCorp, Quest Diagnostics, or the Oklahoma Medical Research Foundation. In patients with low-level antibody titers, it may be beneficial to repeat antibody testing by immunoprecipitation, such as through the Comprehensive Myositis Panel from the Oklahoma Medical Research Foundation or the Euroimmun Autoimmune Inflammatory Myopathies 16 Ag kit.¹⁴

Patients with dermatomyositis will typically present with a heliotrope rash and skin lesions, such as Gottron papules.¹⁵ If there is muscle involvement, muscle pathology shows perifascicular atrophy and perimysial perivascular inflammation.¹⁵ Our patient had a weakly positive TIF1-γ titer of 33 units on the MyoMarker 3 panel (an enzyme-linked immunosorbent assay test) through LabCorp that was believed to represent a false-positive result because she did not have skin or muscle biopsy findings consistent with dermatomyositis. This has 2 implications. First, despite the appropriate designation, myositis-specific antibodies (such as TIF1-γ) can be detected in patients without polymyositis or dermatomyositis.¹² Muscle biopsy is a useful diagnostic tool in atypical presentations; for example, in this case, the differential diagnosis without typical skin findings included dermatomyositis sine dermatitis vs inflammatory myopathy or toxic myopathy. In our patient, the muscle biopsy was critical in arriving at the appropriate diagnosis of immune-mediated necrotizing myopathy. Second, patients with seronegative immune-mediated necrotizing myopathy and patients with dermatomyositis associated with TIF1-γ or NXP-2 antibodies are at increased risk of developing malignancy within 3 years of diagnosis.¹³

While no evidence-based guidelines indicate the type or frequency of cancer screening in patients with inflammatory myopathy, including those with immune-mediated necrotizing myopathies, given the increased risk of malignancy within 3 years of diagnosis, it is important to perform comprehensive cancer screening with mammograms, colonoscopy, or PET scan at initial evaluation and consider annual screening. If patients worsen clinically while on a stable immunosuppressant regimen, thorough re-evaluation for malignancy should be considered.

Autoantibody positivity should be interpreted in the context of clinical and pathologic features. In cases where there are atypical features in the clinical syndrome and autoantibody profile, muscle biopsy can be a valuable tool in clarifying the correct diagnosis. Upregulation of MHC-I on nonnecrotic myofibers is an important and useful pathologic feature identifying inflammatory etiologies in otherwise nonspecific muscle pathologies, such as necrotizing myopathy. While MHC-I upregulation can also be seen in inflammatory muscular dystrophies such as dysferlinopathies, it contributes significant diagnostic value in distinguishing immune-mediated necrotizing myopathies from nonimmune-mediated necrotizing myopathies.