FINAL DIAGNOSIS: ANTISYNTHETASE SYNDROME
Epidemiology and Clinical Presentation
Antisynthetase syndrome (AS) appears to have been first described, as a syndrome, around 1989, and refers to the constellation of symptoms that often appear to occur in association with antibodies against aminoacyl-tRNA synthetases (see below). A variably expressed constellation of findings, with or without myositis, includes a relatively acute disease onset, constitutional symptoms (e.g. fever), Raynaud's phenomenon, Mechanic's hands, arthritis and interstitial lung disease (ILD). Sometimes, it can be difficult to diagnose due to many patients being treated with steroids prior to antibody testing/full development of the disease. The overall prevalence of AS is unknown. The reported annual incidence of polymyositis and dermatomyositis ranges from 2-10 new cases per million persons. The disease affects mainly adults and the sex ratio is about 2:1 female to male patients. Chinoy et al. recently found that anti-aminoacyl-tRNA synthetases are the most common myositis specific antibody in polymyositis (25%) and dermatomyositis (25%), supporting evidence from numerous previous studies.
AS usually occurs with anti-aminoacyl-tRNA synthetases, including Anti-Jo-1 (most common), OJ, EJ, PL-7, PL-12, and KS antigens. These antibodies are usually detected by immunodiffusion or immunoprecipitation. The targets of these antibodies are the aminoacyl-tRNA synthetases which catalyze the attachment of specific amino acids to their cognate tRNAs during protein synthesis.
Variable percentages of patients with anti-aminoacyl-tRNA synthetases were found to have interstitial lung disease (ILD); the true amount of involvement remains poorly defined. In one of the more recent studies, Chinoy et al. found 42% of patients with anti-aminoacyl-tRNA synthetases had ILD. The patients do not need to have all manifestations to have AS. Some patients have relatively little myositis, but more prominent other features, including ILD (3). Some have a complete absence of myositis (4), including patients with anti-Pl-12 antibody (5). AS is not specific to anti-aminoacyl-tRNA synthetases; other antibodies seen include anti-PM-Scl and anti-U1RNP (6), with other antibodies that may prove to be involved as well. Patients may have other antibodies in addition to the anti-synthetases (7). AS patients with associated anti-Ro/SSA antibodies appear to be predisposed to a more severe ILD (8).
Several investigative groups have looked into the interrelationships among myositis subsets, autoantibodies, and the major histocompatibility complex (MHC) class II alleles. Arnett et al., across four different racial groups (including whites, African-Americans, Mexican Americans and Japanese), found a genetic susceptibility to anti-Jo-1 and other myositis specific antibodies in patients with myositis that can be localized within the MHC region to the HLA-DQA1 locus (9). However, Furuya et al found that HLA-DRB1 alleles were associated with development of idiopathic inflammatory myopathies and myositis specific autoantibodies in a Japanese population (10). More recently, O'Hanlon et al. found that there were numerous variations in the associated polymorphisms for the associated genes that may be causing unique responses by the individuals leading to the different syndromes commonly seen in myositis (11).
Treatment and Prognosis
The treatment for AS includes prednisone and/or cyclophosphamide, the latter being especially useful in those patients with ILD. There have been recent studies showing that tacrolimus may also be of benefit (5). In 1997, Lee et al. performed a review of the literature showing that 25-68% of patients with antisynthetase syndrome treated with high dose corticosteroids as part of their initial therapy go into remission, while 6 to 43% appear to relapse.
Tillie-Leblond et al. recently looked at a group of 32 patients who were not initially diagnosed with antisynthetase syndrome who had anti-Jo-1 antibodies present. Some of the patients had a more gradual onset of their disease while others had a more acute onset. Overall, of these patients, one third had ILD progression with respiratory insufficiency, while the rest had more stable ILD (7). In 1988, Arsura et al., performing a Medline survey of patients with polymyositis and dermatomyositis with ILD, found that 40% died after followup of an average of 32 months, which was significantly higher than those patients without ILD. Progressive ILD was the immediate cause of death in 58% of those who died (13). However, more recently Spath et al. found upon following 12 patients with myositis and anti-Jo-1-autoantibodies during the past 14 years that the mortality rate was 8% and deterioration of pulmonary function was found only in the patient with a lethal outcome. The authors of the latter article feel that this may be due to the fact that their patients were included as ILD on the basis of symptoms and radiologic signs of fibrosis without histologically proven fibrosis, as opposed the former article in which they included only cases of histologically proven fibrosis (14). There is no readily available data on the success of a lung transplant with AS.
Due to the impressive clinical acumen of her clinicians, this patient was diagnosed with polymyositis, likely antisynthetase syndrome. During her hospitalization, she received three days of pulse steroids and cyclophosphamide followed by oral prednisone 60 mg and cyclophosphamide 50 mg daily. Her respiratory status and overall clinical status improved during the hospitalization until she was discharged. She continued to improve as an outpatient, returning to work and planning to go to college this year. Although currently still a candidate, she is not being further evaluated for transplant due to her recovery on immunosuppression.
The author would like to thank Dr. Bruce Rabin and Dr. Robyn Domsic for their help with this case.
Contributed by Marian A Rollins-Raval, MD, MPH