Antisynthetase syndrome

Anti-synthetase syndrome is an autoimmune disease, characterized by aminoacyl transfer RNA synthetase antibodies with clinical features that can include interstitial lung disease, myositis, Raynaud’s phenomenon, and arthritis. There is a higher prevalence and increased severity of interstitial lung disease in patients with the anti-synthetase syndrome as compared to other inflammatory myopathies. Diagnosis is made by serological, radiographic, and muscle and/or lung biopsy results. Patients frequently require multi-modality immunosuppressive therapy to manage muscular and pulmonary manifestations of the disease. Careful attention is required to the adverse effects and complications of chronic immunosuppressive therapy, as well as to the disease complications which include progressive interstitial lung disease, pulmonary hypertension, and malignancy. Increased awareness of this syndrome will allow for early diagnosis and treatment improving outcomes in patients.


Introduction
Antisynthetase syndrome (ASS) was first described by Marguerite and coworkers in 1990 [1] . It is a rare idiopathic autoimmune connective tissue disorder characterized by the presence of autoantibodies against the aminoacyl-tRNA synthetase (antiARS) complex with variable clinical presentation. Typically cases present with a triad of interstitial lung disease (ILD), arthritis, and myositis whereas Raynaud's phenomenon, mechanic's hands, and fever are less prevalent. ASS affects women and men in an approximate ratio of 2: 1 and ages from 22 -74 years [2] . Solomon et al. (2011) diagnostic criteria is used to confirm the diagnosis. [3] Required criteria: Presence of anti-aminoacyl tRNA synthetase antibody Plus 2 major or 1 major and 2 minor criteria Major 1) Interstitial lung disease (not attributable to another cause) 2) Polymyositis or dermatomyositis by Bohan and Peter criteria Minor -1) Arthritis 2) Raynaud's phenomenon 3) Mechanic's hands

Case report
A 35-year-old male presented with gradually progressive grade 2 exertional dyspnea and dry cough since 3 years. History of joint pain over bilateral knees, elbows, and wrists with Raynaud's phenomenon affecting fingertips was present since 1.5 years. There was no history of fever, weakness in thighs or shoulder girdle, photosensitivity, oral ulcers or difficulty in swallowing. General physical examination was normal. Cutaneous examination revealed hyperkeratotic, scaly plaques with fissuring over palmar and radial aspect of hands, akin to mechanic s hand (Fig 1 A and B) mild tapering of the left index finger was seen ( Fig  2). Respiratory system examination revealed decreased chest expansion to 3 cm on palpation and fine bibasilar Velcro crepitations (inspiratory) on auscultation. Musculoskeletal system examination was normal with normal muscle power and a normal range of movements was present. Cardiovascular system examination was normal. His complete blood count, liver function test, renal function test, random Blood Sugar, thyroid-stimulating hormone, T3, T4, anti-cyclic citrullinated peptide, phosphokinase levels were within normal limits. Serum VDRL, HIV, HBsAg, and HCV was nonreactive. Electrocardiography, 2D echocardiography, ultrasonography of abdomen and pelvis, X-ray hand (AP view), X-ray ~ 7 ~ www.dermatologypaper.com pelvis (AP view) X-ray bilateral knee joint (AP view) were normal. Chest X-Ray showed patchy consolidation in bilateral lower lobes (fig 3). High resolution computed tomography (HRCT) showed intra and interlobular septal thickening, mild tubular traction bronchiectasis, and diffuse ground-glass opacity in both lower lobes, suggestive of nonspecific interstitial pneumonia (fig 4). Serum anti nuclear antibodies (ANA) profile was positive for antiJO-1 (+++) and antiRO-52(+++). Diagnosis of ASS was confirmed on basis of presence of required criteria (Anti-JO1 antibody) along with one major criteria (ILD) and three minor criteria (Raynauds phenomenon, mechanics hand, arthritis). The patient was prescribed azathioprine 50 mg orally once a day and supportive therapy for 6 months. As there was little clinical improvement, he was given intravenous cyclophosphamide pulse therapy, 500 mg every 4 weeks with regular monitoring. He was maintained on oral prednisolone 0.5mg/kg daily, multivitamins, calcium 500mg+ vitamin D3 250 IU, metered dose inhaler levosalbutamol/levalbuterol 50mcg+ ipratropium 40mcg, emollients and topical clobetasol (0.05%) + salicylic acid cream (3%). Significant improvement was observed in cutaneous lesions and joint pain however there was no improvement in dyspnea.

Discussion
ASS is an idiopathic inflammatory myopathy (IIM). Associated signs and symptoms include ILD, myositis, arthritis, Raynaud's phenomenon, fever and mechanic's hand (Fig 5). A higher prevalence of ILD is seen in ASS relative to other inflammatory myopathies [3] . Incomplete forms, especially initial symptoms may not suggest ASS. ASS can also present with isolated manifestations of either ILD, arthritis, or myositis [4] . Our patient presented with ILD without myositis and fever. In atypical cases inflammatory arthritis may mimic RA. In cases of oesophageal involvement or pulmonary hypertension, overlapping systemic sclerosis should be considered. Several antinuclear antibodies such as anti JO-1, anti-PL-7, anti-PL-12, anti-OJ, anti-EJ, anti-ZO, anti-YRS/Ha and anti-KS are seen. Presence of one or more of the above antibodies is a "required criteria for diagnosis of ASS" (Table-1). Other myositis specific autoantibodies may also be seen in ASS (Fig6) Management of ASS includes systemic corticosteroids 1mg/kg/day as the first-line therapy. Some ASS patients may have corticosteroid resistant myositis or ILD. Azathioprine 1mg/kg/day is a second-line agent. IVIG or MMF (mycophenolate mofetil) can also be used as add on therapy. In acute exacerbations cyclophosphamide 500 mg IV every 4 weeks or Rituximab 1g with an interval of 2 weeks can be used as rescue therapy [9] . The ILD in ASS cases is often severe and rapidly progressive, causing increased morbidity and mortality as compared with other IIMs. Patients with pulmonary hypertension and age greater the 60 years have poor prognostic factors. The most common causes of death are pulmonary fibrosis and pulmonary hypertension. Hence severe and aggressive ILD require multi-modality therapy and lung transplantation is to be considered when the disease is progressive and fails to respond to treatment [8] .   Fig 1(A, B): Mechanic's hand.   Fig 4(A, B): HRCT chest showing diffuse ground-glass opacity in both lower lobes, suggestive of nonspecific interstitial pneumonia.  [4] .
~ 9 ~ www.dermatologypaper.com Table 1: Presence of one or more of the above antibodies is a required criteria for diagnosis of ASS

Myositis-specific antibodies related to ASS Target antigen Significance
Anti-JO-1 histidyl t RNA synthetase The most common antisynthetase antibody, Develops as the classical form. Strong predictor for ILD (70-90%), but also a strong predictor of clinical response to immunobiological drug Anti-PL-7 threonyl t RNA synthetase Increased involvement of the gastrointestinal tract, Raynaud's phenomenon, and ILD. Isolated ILD is typical, but milder compared to anti-PL-12. This happens in myositis as well Anti-PL-12 alanyl t RNA synthetase Increased involvement of the gastrointestinal tract, Raynaud's phenomenon, and ILD. ILD isolated is typical but has a greater burden of ILD and esophageal involvement and a lower chance of developing arthritis and myositis compared to anti-PL-7 Anti-OJ isoleucyl t RNA synthetase ILD is common but responds very well to glucocorticosteroids. Strong association with neoplasia, but without statistical evidence Anti-EJ glycyl t RNA synthetase It develops the classic form with myopathy and ILD and is possibly the one with the lowest association with malignancy Anti-KS asparaginyl t RNA synthetase DPI is frequent, but Raynaud's phenomenon and arthritis are not. Myositis was not evidenced Anti-ZO phenylalanyl t RNA synthetase <1% in ASS, Develops as the classical form.
Anti-YRS or Anti-TyR or anti-Ha tyrosyl t RNA synthetase <1% in ASS, Develops as the classical form.

Conclusion
Antisynthetase syndrome is a lesser known but important and treatable cause of ILD. Unexplained acute respiratory distress syndrome, Raynaud's phenomenon, and mechanic's hands should raise the suspicion of anti-synthetase syndrome for appropriate management to reduce morbidity and mortality of patient.