Abstract
Objective Population-based epidemiology studies about antisynthetase syndrome (ASyS) are lacking. Our aims were to determine the incidence and prevalence of ASyS and assess malignancy risk among patients following ASyS diagnosis.
Methods A retrospective, population-based cohort of adults with incident ASyS residing in Olmsted County, Minnesota, in 1998-2019, was assembled. Fulfillment of Solomon classification criteria for ASyS and clinical data were collected by manual chart review. Patients were followed until death, migration from the area, or December 31, 2019. Malignancy was defined by physician diagnosis in the medical record. Incidence rate was age- and sex-adjusted to the 2010 US White population. Point prevalence rate was obtained on January 1, 2015.
Results Thirteen patients with ASyS were identified (7 [54%] female, 13 [100%] White, median age 44.9 [IQR 41.9-58.3] years). The age- and sex-adjusted incidence of ASyS was 0.56 (95% CI 0.25-0.87) per 100,000 population. Incidence was highest in the 50-59 age group. Age- and sex-adjusted prevalence was 9.21 per 100,000 (95% CI 3.44-14.98). Two of 13 (15%) were diagnosed with malignancy within the follow-up interval and none within 3 years of ASyS diagnosis. At median 11.9 (IQR 7.0-13.4) years of follow-up, 12/13 (92%) of patients were alive.
Conclusion ASyS is rare, with an incidence of 0.56 per 100,000 population and prevalence of 9.21 per 100,000. In this cohort, incidence was similar between male and female individuals, and was highest in persons aged 50-59 years. None of the patients developed malignancy within 3 years of ASyS diagnosis.
Antisynthetase syndrome (ASyS) is a distinct subgroup of the idiopathic inflammatory myopathies (IIMs), characterized by myositis, interstitial lung disease (ILD), inflammatory arthritis, Raynaud phenomenon, and aminoacyl tRNA synthetase autoantibody. The condition was defined in 1990.1,2 The Jo-1 antibody, present in 10% to 40% of patients with ASyS, and directed against the histidyl-tRNA synthetase, is the most commonly associated antibody.3,4 Other more recently associated antibodies include PL-7, PL-12, EJ, OJ, Ha, Ks, and Zo.3,4
Population-based epidemiology studies of ASyS are lacking. The estimated prevalence of the Jo-1 antibody is 1.5 per 100,000, yet incidence and prevalence of the disease are unknown.1,3,4 Epidemiological studies have been challenging due to the heterogeneity of the disease and lack of consensus-driven, validated criteria for ASyS.5,6 The discovery of additional autoantibodies that define ASyS, as well as developments in imaging and other diagnostic testing, may be contributing to an increase in diagnosed cases.
Dermatomyositis (DM), an autoimmune condition characterized by muscle inflammation and characteristic skin rashes that share some features of ASyS, has been associated with increased risk of malignancy, particularly in the first 3 years of disease.7,8 Despite many cases of malignancy in patients with ASyS reported in the literature, estimates of frequency vary widely, from 1.7% to 19.4%.9,10 To date, there is no consensus on the association between ASyS and malignancy, particularly in the early stages of disease. The need for specific cancer screening recommendations for patients with newly diagnosed ASyS is largely unknown, although recently published, expert-driven consensus guidelines for cancer screening in newly diagnosed IIMs has classified patients with ASyS to be at low risk for occult cancer.11
Our aims were to determine the incidence and prevalence of ASyS in a well-defined geographic area over a 22-year period, and to assess malignancy risk among patients with incident ASyS within 3 years of diagnosis.
METHODS
A retrospective, population-based cohort was assembled, comprising adults with incident ASyS residing in Olmsted County, Minnesota, between January 1, 1998, and December 31, 2019. Patients were identified using International Classification of Diseases, 9th revision (ICD-9) and ICD-10 codes corresponding to relevant conditions. The electronic medical charts of patients who had a positive Jo-1 antibody, and of all patients with ICD codes corresponding to inflammatory myopathy (G72.41) or myositis (710.3, 710.4, D89.89, G72.41, G72.49, M33.10, M33.11, M33.19, M33.20, M33.21, M33.29, M33.90, M33.91, M33.99), were reviewed manually by study personnel (CMC, LW). A random sampling of 50 patients with ICD codes corresponding to other myopathy (359.9, G72.89, G72.9, G73.7) were reviewed manually for inclusion as well, to ensure no missed cases of ASyS. Fulfillment of the Solomon criteria for ASyS12 and clinical data were collected by manual chart review (CMC, LW), through the validated Rochester Epidemiology Project (REP) medical records linkage system.13 Cases of “incomplete ASyS” were not included for the purposes of this study.10 Patients who met criteria but were diagnosed with an alternative disease were excluded from the study. ILD was defined by physician diagnosis in the medical record, inclusive of findings on pulmonary function testing, radiography, and/or computed tomography scan. Malignancy was defined by physician diagnosis in the medical record.
Patients were followed until death, migration from the area, or December 31, 2019. Descriptive statistics were used to describe the demographic and clinical characteristics of patients with ASyS. Age-specific and sex-specific incidence rates were calculated using the number of incident cases as the numerator, and population counts from the REP census as the denominator.14 Age- and sex-specific prevalence rates were calculated using the number of prevalent cases on January 1, 2015, as the numerator, and population counts from the REP census as the denominator.14 Incidence and prevalence rates were age- and sex-adjusted to the 2010 US White population. In order to compute 95% CIs for incidence and prevalence rates, it was assumed that the number of cases followed a Poisson distribution. Time-to-event analysis methods were not used to summarize characteristics that developed during follow-up due to the small sample size. Statistical analyses were performed using SAS version V.9.4 (SAS Institute).
RESULTS
Thirteen patients with ASyS who fulfilled Solomon et al criteria12 in the geographic area were identified in the 22-year study period. Seven (54%) patients were female, 13 (100%) were White, and median age was 44.9 (IQR 41.9-58.3) years at the time of meeting the criteria.
Thirteen patients (100%) had positive antinuclear antibody, and 12 (92%) had positive Jo-1 antibody (Figure 1A). A myositis-specific panel was positive in 1 out of 4 patients showing PL-7 antibody. At time of meeting criteria, 4/13 patients (31%) had fever, 11 (85%) had ILD diagnosed by a physician, 11 (85%) had myositis, and 6 (46%) required oxygen supplementation. Of the 11 patients who ever developed ILD, 8 patients (73%) had a nonspecific interstitial pneumonia pattern (Figure 1B). Of the 11 patients with myositis, 6 (55%) had a positive electromyogram, 1 (9%) had positive muscle magnetic resonance imaging, and 5 (45%) had muscle biopsy performed, all of which demonstrated inflammatory myopathy.
Clinical characteristics of 13 patients with antisynthetase syndrome (1998-2019). (A) Autoantibodies detected. (B) Patterns of interstitial lung disease. ANA: antinuclear antibody; ILD: interstitial lung disease; RNP: ribonucleoprotein.
At any point during the disease course, all 13 (100%) patients were treated with corticosteroids, 9 (69%) with mycophenolate mofetil, 8 (62%) with azathioprine, 6 (46%) with methotrexate, 3 (23%) with rituximab, 2 (15%) with intravenous immunoglobulin, and 1 (8%) with cyclophosphamide.
The age- and sex-adjusted incidence of ASyS was 0.56 (95% CI 0.25-0.87) per 100,000 population (Table 1). The age-adjusted incidence was 0.59 (95% CI 0.15-1.03) per 100,000 for female individuals, and 0.52 (95% CI 0.10-0.94) per 100,000 for male individuals. Incidence rate was highest in the 50-59 age group, at 1.01 per 100,000 population. Age- and sex-adjusted prevalence of ASyS on January 1, 2015, was 9.21 per 100,000 (95% CI 3.44-14.98; Table 2).
Incidence of antisynthetase syndrome in a population-based cohort, according to age at fulfilling disease criteria12 (1998-2019).
Prevalence of antisynthetase syndrome in a population-based cohort of patients, by age (January 1, 2015).
Within the follow-up interval, 2/13 (15%) were diagnosed with a malignancy (Hodgkin lymphoma, leiomyosarcoma), neither of which was within 3 years of ASyS diagnosis. Mean time to malignancy diagnosis from ASyS criteria was 52 (range 40-64) months. At a median 11.9 (IQR 7.0-13.4) years of follow-up, 12/13 (92%) of patients were alive.
DISCUSSION
ASyS, characterized by an aminoacyl tRNA synthetase autoantibody, myositis, ILD, inflammatory arthritis, and Raynaud phenomenon, is a distinct disease entity initially defined in 1990.1,2 Since then, tRNA synthetase antibodies other than the Jo-1 have been identified and described,3,4 yet the incidence and prevalence of ASyS itself has been unknown. Epidemiologic studies have been challenging due to the rarity of the disease, lack of consensus classification criteria, overlapping features with other rheumatologic conditions, and lack of ICD code specific to ASyS. Our present study identified 13 patients with ASyS who fulfilled the Solomon criteria12 during a 22-year study interval between 1998 and 2019. To our knowledge, ours is the first population-based epidemiological study demonstrating that the incidence of ASyS in a geographically based population is 0.56 per 100,000 population, after adjusting for age and sex. The prevalence of ASyS in this cohort on January 1, 2015, was 9.2 per 100,000.
The results of this current study are in line with estimates of incidence of all IIMs, ranging from 11 to 660 per 1 million person-years,15 as ASyS represents a subset of these conditions. Similarly, prevalence estimates for IIM range from 25 to 34 per 100,000 individuals15 in other North American cohorts, with a prevalence of ASyS expected to be lower than that of IIM conditions as a whole. The highest incidence of ASyS was observed in the fifth and sixth decades of life, as observed in IIM conditions as a whole.15 A slight predominance of female (54%) vs male patients with incident ASyS in this cohort differs from prior research reporting a 2:1 ratio of female to male individuals.12,15 The majority of patients in this cohort (92%) had a positive Jo-1 autoantibody, and only 1 of the 13 patients had non–Jo-1 tRNA synthetase antibody detected (PL-7). The other known autoantibodies associated with ASyS were not detected in this population; this may be a reflection of the study’s small sample size and low prevalence overall,6,15 as well as lack of commercially available testing for these antibodies until the later years of this study interval.
An important finding of this study was the fact that in this cohort, there were no cases of associated malignancy within the first 3 years after fulfilling criteria for ASyS. Although a malignancy risk in DM has been clearly established, with approximately 25% of patients with DM being diagnosed with a malignancy within 3 years,5,6 data supporting a potential relationship between ASyS and malignancy has been mixed. Reports exist of patients with ASyS who have malignancies concurrently diagnosed, including lung, breast, ovarian, renal, liver, and colon cancer, and melanoma.9,10,16-18 However, a large cohort of 233 patients with ASyS by Hervier et al found cancer association no higher than that of the general population.10 Further, a large metaanalysis by Oldroyd et al involving 69 myositis studies found that the presence of ILD and any anti-tRNA synthetase antibody—in particular Jo-1—was significantly associated with a lower risk of cancer.19 In the current study, 2/13 (15%) patients with ASyS were diagnosed with a malignancy (Hodgkin lymphoma, leiomyosarcoma) within the follow-up interval, with a mean time from meeting ASyS criteria to malignancy diagnosis of 52 (range 40-64) months. The data from this cohort does not suggest an association between development of ASyS and malignancy.
Strengths of this study include a novel investigation into the epidemiology of ASyS. Other strengths include a geographically based cohort of patients, with access to records from nearly all medical facilities in the area13 to allow for comprehensive review despite a retrospective design, a 22-year study interval with median 11.9 years of follow-up for patients, and manual medical record review by physicians.
The primary limitations of this study are its retrospective nature and small cohort size of 13 patients, which reflects the rarity of the disease. A longer study interval was not feasible due to the relatively recent identification of ASyS. Additionally, there is potential for missed cases due to developments in testing for antisynthetase antibodies, which did not become commercially available until the later years of this study’s interval, as well as the heterogeneous nature of ASyS, with no consensus definition.5 This risk has been minimized by the use of the Solomon criteria for all included cases and by use of manual medical chart review.12 Finally, a mortality analysis was not feasible due to only 1 death observed in the study cohort.
In summary, ASyS is rare, with an incidence of 0.56 per 100,000 population and prevalence of 9.21 per 100,000. Incidence appears similar in our cohort between male and female individuals, differing from previous estimates of higher incidence in female individuals, and was highest in persons aged 50-59 years. None of the patients in this cohort developed malignancy within 3 years of ASyS diagnosis.
ACKNOWLEDGMENT
The authors wish to acknowledge Li Wang, MD, PhD (The First Affiliated Hospital of USTC/Anhui Provincial Hospital, China), for her significant contributions to this project.
Footnotes
CONTRIBUTIONS
CMC: conceptualization, data curation, investigation, project administration, validation, visualization, writing – original draft, writing- review & editing; CAH: data curation, formal analysis, investigation, validation, visualization, writing- review & editing; CSC: data curation, formal analysis, investigation, methodology, supervision, validation, visualization, writing- review & editing; JHR: conceptualization, investigation, validation, writing- review & editing; FCE: conceptualization, data curation, investigation, methodology, project administration, supervision, validation, visualization, writing – original draft, writing- review & editing.
FUNDING
This study was made possible by the Clinical and Translational Science Awards Grant UL1 TR002377 from the National Center for Advancing Translational Sciences, a component of the National Institutes of Health (NIH). This study used the resources of the Rochester Epidemiology Project (REP) medical records linkage system, which is supported by the National Institute on Aging (AG 058738), by the Mayo Clinic Research Committee, and by fees paid annually by REP users. The content of this article is solely the responsibility of the authors and does not represent the official views of the NIH or the Mayo Clinic.
COMPETING INTERESTS
The authors declare no conflicts of interest relevant to this article.
ETHICS AND PATIENT CONSENT
This study was approved by the institutional review boards of Mayo Clinic (20-001744) and Olmsted Medical Center (014-OMC-20). A waiver of informed consent was granted for this minimal risk study.
- Accepted for publication December 18, 2024.
- Copyright © 2025 by the Journal of Rheumatology
