A 62‐Year‐Old Woman with A History of Muscle Pain and Skin Rash for 1 Month

Clinical History

The patient was a 62‐year‐old woman who presented at the hospital with a one‐month history of muscle pain and skin rash. Before this visit, she had experienced fever for 2 months. She had no other underlying medical condition except for rheumatoid arthritis which had been treated for over 20 years. Physical examination revealed mild symmetrical proximal muscle weakness of both upper and lower extremities (Medical Research Council grade 4). Erythema was observed in lower legs. Serum creatine kinase (CK) was 2048 U/L (normal range 32–180 U/L). Muscle biopsy was performed in the left tibialis anterior muscle.

Microscopic Pathology

On H&E (Figure 1A,B), there is moderate fiber size variation ranging from 20 to 80 µm. The perimysium is generally edematous and fragmented. Mild endomysial fibrosis is observed. Necrotic and regenerating fibers are common; most of them locate at perifascicular regions. Focal endomysial and perivascular lymphocytic infiltration is noted, but not surrounding or invading into non‐necrotic fibers. Macrophages are associated with necrotic fibers. Fibers with internalized nuclei are present, 20%. There are no structural abnormalities such as ragged‐red fibers, nemaline bodies or rimmed vacuoles identified by modified Gomori Trichrome (not shown). The intramyofibrillar network demonstrated by NADH are well‐organized except for the necrotic and regenerating fibers (not shown). Alkaline phosphatase activity is seen in perimysium in addition to regenerating fibers (Figure 1C). There is no fiber type grouping demonstrated by ATPase stainings. Others stainings including acid phosphatase, COX, SDH, oil red O, PAS, NSE and AChE show no additional abnormalities. Immunohistochemical study for HLA‐DR shows scattered cytoplasmic positivity, especially in perifascicular regions (Figure 1D) while staining for myxovirus resistant protein A (MxA) is negative (not shown). What is your diagnosis?

Figure 1.

 

Diagnosis

Immune‐mediated necrotizing myopathy, INM or IMNM (Synonym: necrotizing autoimmune myopathy, NAM).

Most likely anti‐synthetase myopathy (ASM).

Discussion

Idiopathic inflammatory myopathy (IIM) is currently classified into four major groups including iNM, dermatomyositis (DM), inclusion body myositis (IBM) and polymyositis (PM). Without detailed clinical information and laboratory study, a combination of skin lesions and acute to subacute muscle weakness with high CK level sometimes mislead pathologists to the diagnosis of DM although clinical findings and muscle biopsy pathology are not that typical for the disease. In DM, the characteristic skin lesions include periorbital violaceous erythema (heliotrope rash) and raised violaceous scaly eruptions on the knuckles (Gottron's sign/papule). V‐shape erythematous rash on anterior chest as well as erythematous rash on the face, knees, elbows, malleoli and neck are also common, but not specific for the disease. In fact, skin lesions can be presenting symptoms of anti‐synthetase myopathy (ASM), a distinct subgroup of IIM identified by specific autoantibodies directed against tRNA‐synthetase eg. anti‐Jo‐1, anti‐PL‐7, anti‐PL‐12, anti‐OJ, anti‐EJ, anti‐KS, anti‐Zo and anti‐Ha; the most common autoantibody among this group is anti‐Jo‐1 1, 2. The other clinical symptoms in ASM include interstitial lung disease, arthritis, Raynaud's phenomenon and mechanic's hands 2. Anti‐Jo‐1 antibody‐positive myopathy, as well as some of ASMs associated with autoantibodies against non‐Jo‐1 synthetases, is pathologically characterized by perifascicular necrotizing myopathy 2, 4. This can be superficially resembling DM as the prominent findings in both entities are perifascicular pathology. Usually, perimysium and adjacent endomysium alkaline phosphatase reactivity is present in anti‐Jo‐1 antibody‐positive myopathy, whereas endomysial microangiopathy, such as perifascicular lymphocytic infiltration and vascular C5b‐9 expression, is present in DM 1. Perifascicular COX‐negative fibers are also favor the diagnosis of DM. Interestingly, perifascicular myofiber immunohistochemical positivity for MxA has been introduced as an auxiliary test for DM as MxA is one of type 1 interferon‐inducible proteins highly expressed in perifascicular myofibers of DM patients 3. Moreover, perifascicular HLA‐DR expression is recently described as a unique finding in ASM 1. In summary, our patient presented with acute onset proximal muscle weakness and skin erythema with questionable H&E pathology; absence of perifascicular COX‐negative fibers, negative MxA immunostaining, increased perimysial alkaline phosphatase activity and mild perifascicular HLA‐DR positivity are suggestive of ASM. In our patient, positive anti‐Jo‐1 antibody is confirmed. Precise distinction between ASM and DM is important because diagnostic implications of ASM and DM can significantly differ with potential of extramuscular manifestations, including life‐threatening interstitial pneumonia in the former and malignancy association in the latter.