2020 NPA-08

This case was originally published in 2020. The information provided in this case was accurate and correct at the time of initial program release. Any changes in terminology since the time of initial publication may not be reflected in this case.

A 42-year-old woman with a clinical history of Raynaud phenomenon presented with one month of progressive skeletal muscle weakness and myalgias. Neurologic exam revealed bilateral proximal lower extremity weakness, normal sensation, and normal reflexes. Creatine kinase (CK) was elevated to 3042 U/L (normal range 22 to 198 U/L). Electromyography (EMG) showed evidence of an irritable myopathy with fibrillation potentials and sharp waves. A muscle biopsy was performed.

Tissue Site
Left quadriceps muscle

The whole slide image provided is an H&E-stained section of frozen quadriceps skeletal muscle.

The muscle biopsy findings are diagnostic of antisynthetase syndrome-associated myositis. Subsequent antibody testing of the patient’s serum showed significantly increased anti-Jo-1 antibodies at >8.0 U (>1.0 U positive; >8.0 U upper limit of detection). Therefore, the final diagnosis is anti-Jo-1 myositis.

Antisynthetase syndrome (ASS) is caused by autoantibodies targeting aminoacyl-tRNA synthetases, which include Jo-1, PL-7, PL-12, OJ, EJ, KS, Wa, YRS, and Zo. Patients with antibodies against one of the tRNA synthetases can present with various combinations of clinical manifestations including myositis, interstitial lung disease (ILD, nonspecific interstitial pneumonia pattern most common), arthritis, Raynaud phenomenon, “mechanic’s hands,” fever, and/or arthralgias. Rarely, ASS is paraneoplastic. Anti-Jo-1 antibodies are the most frequent cause of ASS overall, occurring in 20% to 30% of patients, and are most commonly associated with myositis. ASS due to anti-PL-7 or anti-PL-12 (the second and third most prevalent antibodies) often shows more severe lung disease and less severe myositis compared to anti-Jo-1-related disease.

Clinically, anti-Jo-1 myositis is characterized by progressive proximal skeletal muscle weakness and myalgia. EMG shows myopathic changes, often with evidence of an irritable myopathic pattern, and CK is typically elevated, sometimes significantly. Autoantibody testing for ASS-related antibodies is widely available, and some of the more common antibodies are included in larger “myositis panels” along with dermatomyositis (DM)-related and immune-mediated necrotizing myopathy (IMNM)-related antibodies. Approximately 80% of anti-Jo-1 myositis patients develop ILD and have a four-fold higher mortality rate compared to the general population due to this pulmonary complication. Patients can present with myositis prior to clinically apparent ILD; therefore, the pathologist can greatly assist by suggesting a pulmonary workup in any patient suspected of having ASS-associated myositis. Treatment involves immunosuppressive and immunomodulatory agents with variable responses.

Classically inflammatory myopathies have been separated into three diagnostic categories: DM, polymyositis, and inclusion body myositis, with ASS falling within the polymyositis or DM categories. However, modern classification schemes have suggested ASS-associated myositis is best separated into its own category due to unique characteristics such as anti-tRNA synthetase antibodies, concomitant ILD, and conspicuous perifascicular myofiber involvement.

Perifascicular involvement seen in muscle biopsies from patients with ASS-associated myositis, and particularly anti-Jo-1 myositis, is characterized by necrosis with phagocytosis of perifascicular myofibers (Image A, Image B, Image C, and Image D). Regenerating fibers are commonly seen associated with necrotic fibers. NADH staining can highlight perifascicular myofibers darkly (Image B), and necrotic fibers can also be highlighted with modified Gomori trichrome staining, which in this case also shows red cytoplasmic inclusion bodies in damaged myofibers (Image D). Lymphocytic inflammation extending from the perimysium into the endomysium can be seen in up to 50% of cases, but lymphocytic inflammation was not a prominent feature of this patient’s biopsy. Another characteristic finding is fragmentation and macrophage-predominant inflammation within the perimysial connective tissue (Image E). This can be nicely highlighted with acid phosphatase and alkaline phosphatase staining. MHC class I (HLA-ABC) immunostaining shows sarcolemmal and sarcoplasmic myofiber expression in a perifascicular pattern with strongest staining in the perifascicular region and less positivity towards the center of fascicles (Image F). Complement C5b-9 (MAC) immunodeposition can be seen in perifascicular myofibers and capillaries as well (Image G). Immunostains for inclusion body myositis markers (TDP43, p62, neurofilament SMI-31, ubiquitin) are negative in this case (not shown). Ultrastructural analysis of ASS-associated myositis often allows for identification of myonuclear actin filament inclusions that are unique and not seen in other idiopathic inflammatory myopathies.

Due to perifascicular myofiber involvement, ASS-associated myositis can be mistaken for a DM spectrum disease. However, the perifascicular necrosis and perimysial fragmentation with macrophage-predominant inflammation seen in ASS are helpful distinguishing factors compared to the perifascicular atrophy more classic of DM. This distinction can be difficult, and a diagnosis of “myositis with perifascicular pathology” can be rendered with a comment suggesting serum testing for both DM- and ASS-related antibodies. Of importance, both DM and ASS-associated myositis patients treated with immunosuppression or immunomodulators prior to the time of biopsy may only show perifascicular MHC class I expression without any obvious changes on H&E, making the widespread utilization of this immunostain highly useful.

Anti-Jo-1 myositis is an important diagnostic consideration in the workup of muscle biopsies, particularly with the high frequency of patients biopsied for suspected inflammatory myopathies. Recognition of a perifascicular pattern with necrosis predominating over atrophy and perimysial fragmentation with macrophages will assist in distinguishing this entity from DM spectrum diseases. This diagnostic separation from DM is clinically important due to the frequent association with life-threatening interstitial lung disease and allows the pathologist to play a significant role in the workup and treatment of these patients.

• Anti-Jo-1 autoantibodies are the most common cause of antisynthetase syndrome-associated myositis.
• Anti-Jo-1 myositis patients very commonly have associated ILD, which can be life-threatening.
• The main diagnostic features of anti-Jo-1 myositis are perifascicular necrosis, perimysial fragmentation with macrophage infiltration, perifascicular MHC class I expression, and perifascicular complement C5b-9 deposition.
• Anti-Jo-1 myositis can be distinguished from dermatomyositis due to the presence of perifascicular necrosis and perimysial fragmentation versus perifascicular atrophy.

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