Additional Investigation After the Muscle Biopsy Diagnosis

Given the biopsy findings and the presence of anti-Jo-1 autoantibody, the patient had computed tomography (CT) of chest, which showed patchy ground glass opacities, minimal reticulation, bronchiectasis, and mild honeycombing at the bilateral lung bases. Minimal ground glass opacities were also noted in the lingula. The findings are consistent with interstitial lung disease (ILD). CT of abdomen and pelvis was unremarkable. The age- and gender-appropriated cancer screening was unrevealing. During the follow up visit, she reported intermittent left hand coldness and cyanosis. Angiography revealed left brachial artery occlusion. Transesophageal echocardiogram (TEE) did not reveal any cardioembolic source.

Final Diagnosis

Antisynthetase Syndrome

Patient Follow-up

The patient was treated with Prednisone 40 mg once daily. She underwent left axillary-to-radial bypass using a non-reversed left greater saphenous vein harvested from the left leg. She was also treated with Coumadin. Her limb weakness and skin peeling at the fingertips (mechanic’s hand) resolved 2 months after starting steroids. The symptoms of intermittent coldness and cyanosis of the left hand also resolved. She remained symptom free from her ILD standpoint. Chest CT abnormalities improved. The dose of prednisone was gradually tapered down to 20 mg daily. She tolerated the steroids well. She did not want to take a chronic immunosuppressive agent to spare the steroids use. She continued to do well 4 years after the initiation of the steroids treatment.

Discussion

The classification of idiopathic inflammatory myopathies (IIM) has been continuously evolving owing to the advances in the characterization of muscle inflammatory cell infiltrates, muscle pathology phenotypes, and autoantibody associations [1–12]. Based on the clinical presentation, muscle pathological features, and serological findings, IIM are currently classified into 5 distinct subtypes which include inclusion body myositis (IBM), polymyositis (PM) , dermatomyositis (DM), immune-mediated necrotizing myopathy (IMNM), and antisynthetase syndrome (ASS) [1, 10, 13]. The percentage of each subtype varies in different study cohorts [9, 14]. IMNM is the most common subtype in the large Japanese (177/460, 38.5%) [14] and French (91/260, 35.0%) [9] cohorts. This is followed by IBM in the Japanese cohort (73/460, 15.9%) and French cohort (77/260, 29.6%). DM and ASS account for 12.2% and 11.1%, respectively, in the Japanese cohort, and 20.0% and 15.4%, respectively, in the French cohort. PM is rare, accounting for 4.1% in the Japanese cohort but none in the French cohort [9, 14], as most of the PM cases fall into IMNM or ASS after these 2 subtypes have been added to the IIM classification list [9]. In addition, PM associated with connective tissue diseases is often called “overlap myositis” rather than PM. Besides IIM, inflammatory myopathies also include rare eosinophilic fasciitis, focal myositis, and sarcoid granulomatous myositis [1].

Autoantibodies play an important role in shaping the current classification of IIM [1]. They correlate with the severity of muscle disease, extra-muscular manifestations, muscle pathology phenotypes, cancer risk, and treatment response [9, 14]. There are 16 myositis-specific autoantibodies associated with IIM, 8 with ASS, 5 with DM, 2 with IMNM, and 1 with IBM. The myositis-specific autoantibodies associated with ASS target aminoacyl-tRNA synthetases, including histidyl (Jo-1), threnyl (PL-7), alanyl (PL-12), isoleucyl (OJ), glycyl (EJ), asparaginyl (KS), phenylalanyl (ZO), and tyrosyl (YRS/HA) tRNA synthetases [15]. The 5 myositis-specific autoantibodies associated with DM target complex nucleosome remodeling histone deacetylase (Mi-2), melanoma differentiation-associated gene 5 (MDA5), small ubiquitin-like modifier activating enzyme (SAE), nuclear matrix protein 2 (NXP2), and transcription intermediary factor 1γ (TIF-1γ). The two myositis-specific autoantibodies associated with IMNM target signal recognition particle (SRP) and anti-3-hydroxy-3-methyglutaryl-coenzyme A reductase (HMGCR). Anti-NT5C1A antibody is associated with IBM, but it can also be present in Sjogren’s syndrome and systemic lupus erythematosus (SLE). Myositis-associated antibodies include ANA, anti-Ro/SSA, anti-PM-Scl, anti-Ku, and anti-U2 snRNP.

IIM, except for IBM which is discussed in a separate chapter in this book, are autoimmune myopathies that manifest subacute, progressive, proximal limb weakness. While DM can affect both children and adults, PM, IMNM, and ASS predominantly affect adults. These subtypes also differ in the muscle disease severity, extra-muscular manifestations, serum autoantibody association, muscle biopsy features, and treatment response. In general, the muscle disease is mild in ASS but relatively severe in IMNM, especially in SRP-myopathy and statin-naïve HMGCR-myopathy which are discussed in a separate chapter. DM has a wide spectrum, which can be mild or refractory. Serum CK level is usually markedly elevated in IMNM and ASS, less elevated in PM and DM, and can be normal in DM. EMG typically shows an irritable myopathy. Extra-muscular manifestations are a feature of DM and ASS, less commonly seen in autoantibody-negative IMNM, and rare in autoantibody-positive IMNM. Typical skin lesions seen in DM include Gottron papules in finger knuckles, heliotrope erythema in eyelids, and rash in cheek, chest, shoulders, upper arms, and thighs. The presence of anti-MAD-5 autoantibody is associated with severe ILD, skin ulcers, and arthritis but mild muscle weakness. Calcinosis is mainly seen in juvenile DM and associated with anti-NXP-2 autoantibody. The presence of anti-TIF-1γ autoantibody is associated with a high risk of developing malignancies.

ASS is characterized by the presence of anti-tRNA synthetase autoantibodies, myositis, ILD, non-erosive arthritis, mechanic’s hands, and Raynaud’s phenomenon [8, 16]. The diagnostic criteria of ASS was developed in 2010 [17] and revised in 2011 [18]. To be diagnosed with ASS, one must have an anti-tRNA synthetase autoantibody and meet two major or one major and two minor criteria. The major criteria include ILD and myositis. The minor criteria include arthritis, Raynaud’s phenomenon, and mechanic’s hands. Therefore, the diagnosis of ASS requires clinical, serological, radiological, and pathological evaluation which may include serum CK and myositis antibody panel, NCS/EMG, high resolution computed tomography (HRCT) of chest, and muscle or lung biopsy. Our patient had anti-Jo-1 antibody and presented with myositis, arthralgia, mechanic’s hands, and ILD, typical for ASS. In addition, our patient also had vasculopathy with left brachial artery occlusion. Vasculopathy is a known extra-muscular manifestation in dermatomyositis [19]; it has also been reportedly in association with ASS [20].

ASS has a female predominance with a mean age at onset of 60.2 years in one study cohort [21]. The most common manifestation in ASS is ILD with a prevalence of 86%, followed by myositis (73%) and arthritis (60%) [22]. Mechanic’s hands with hyperkeratosis and scaling are common but often subtle. ILD is associated with the high morbidity and mortality of the disease. The cancer risk in ASS is low. Anti-Jo-1 autoantibody is by far the most common autoantibody in ASS. Anti-PL-7, anti-PL-12, anti-OJ, and anti-EJ autoantibodies are less common. Other autoantibodies are rare. While anti-Jo-1, anti-EJ, and anti-PL-7 autoantibodies are most often associated with myositis, anti-PL-12 autoantibody is often associated with amyopathic DM or ILD [23].

Muscle biopsy is useful to support the diagnosis of ASS myositis and to rule out other muscle diseases. The characteristic muscle pathological changes seen in ASS myositis are damages to both myofibers and perimysial connective tissue. Inflammation , when present, is most commonly perivascular in the perimysium (Figs. 5.1b and 5.2A1 and B1) that can extend into nearby endomysium. However, cases of predominantly endomysial inflammation with lymphocyte rimming viable myofibers are present (Fig. 5.2C1). Acute myofiber damages (i.e. necrotic fibers, myophagocytic fibers, regenerating fibers) can be scattered throughout but more frequent in the perifascicular region (Fig. 5.2A1). The preferential involvement of perimysial fibers is often more evident on the MHC1 and C5b-9 immunostains. MHC1 may show diffuse or patchy upregulation in myofibers, with perifascicular accentuation (Fig. 5.2A2, B2, and C2). C5b-9 shows strong sarcoplasmic reactivity in necrotic fibers (Fig. 5.2A3 black arrows), and sarcolemmal reactivity in viable but abnormal perifascicluar myofibers (Fig. 5.2A3 red arrows). True perifascicular atrophy with uniform small atrophic fibers (Fig. 5.1d) is uncommon in ASS myositis. Rather, the presence of frequent small regenerating fibers (highlighted by alkaline phosphatase stain, Fig. 5.2A4 arrows) interspersed by normal sized myofibers in the perifascicular region may give the appearance of patchy, uneven perifascicular atrophy (Fig. 5.2A1). Chronic myopathic changes (i.e. split fibers, hypertrophic fibers, interstitial fibrosis) are usually absent. The perimysial connective tissue damage is often widespread, best viewed in alkaline phosphatase stain (Figs. 5.1c, 5.2A4 and B4). Perimysial capillary abnormalities , including endothelial tubuloreticular inclusions (Fig. 5.2A5, arrow) and capillary C5b-9 deposition (Fig. 5.2A3, yellow arrows) are also common findings, although usually less pronounced than those in dermatomyositis. Intranuclear actin aggregate (Fig. 5.2B5, arrow) has been reported as a specific finding in ASS myositis [24].

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