Clinical manifestations in patients with antibody to PL-12 antigen (alanyl-tRNA synthetase)

doi:10.1016/0002-9343(90)90149-8

The American Journal of Medicine

Volume 88, Issue 3, March 1990, Pages 241-251

https://doi.org/10.1016/0002-9343(90)90149-8 Get rights and content

Abstract

purpose: Anti-PL-12 antibody is directed at the enzyme alanyl-tRNA synthetase (ARS). Studies have clearly associated anti-Jo-1, also directed at an aminoacyl-tRNA synthetase (histidyl-tRNA synthetase), with a subgroup of myositis marked by a high frequency of interstitial lung disease (ILD) and arthritis. A similar syndrome has been reported in patients with antibodies to PL-12, but few patients have been studied. We describe the clinical manifestations in a new series of patients with antibody to PL-12.

patients and methods: Sera from patients with polymyositis and sora found to contain anticytoplasmic antibodies were screened for antibody to PL-12 by testing for inhibition of ARS enzymatic activity by serum, and by immunoprecipitation.

results: Nine sera inhibited ARS. These nine plus two additional sera with anticytoplasmic antibodies immunoprecipitated an identical pattern of tRNAs and a polypeptide of 110 kd. Of the 10 patients that could be evaluated, eight had some evidence of myositis, including six that satisfied the criteria for myositis. Three of these six, all with dermatomyositis, had severe muscle involvement. Eight of the 10 patients had radiographic evidence of pulmonary fibrosis, and seven of the eight had clinical pulmonary impairment, including four with clinically severe ILD. Joint manifestations were found in five patients, and arthritis was the only clinical problem in one patient.

conclusion: We conclude that anti-PL-12, like anti-Jo-1 and anti-PL-7, was frequently associated with the “Jo-1 syndrome” of myositis with ILD. ILD was a major clinical problem in this group of patients.

References (53)

IN Targoff
Laboratory manifestations of polymyositis/dermatomyositis
Clin Dermatol
(1988)
T Biswas et al.
An enzyme-linked immunosorbent assay for the detection and quantitation of anti-Jo-1 antibody in human serum
J Immunol Methods
(1987)
CA Wasicek et al.
Polymyositis and interstitial lung disease in a patient with anti-Jo-1 prototype
Am J Med
(1984)
J Wilusz et al.
Autoantibodies specific for U1 RNA and initiator methionine tRNA
J Biol Chem
(1986)
PE Duncan et al.
Fibrosing alveolitis in polymyositis
Am J Med
(1974)
RJ Fergusson et al.
Dermatomyositis and rapidly progressive fibrosing alveolitis
Thorax
(1983)
S Songcharoen et al.
Interstitial lung disease in polymyositis and dermatomyositis
J Rheumatol
(1980)
H Takizawa et al.
Interstitial lung disease in dermatomyositis: clinicopathological study
J Rheumatol
(1987)
EJ Walker et al.
Improved detection of anti-Jo-1 antibody, a marker for myositis, using purified histidyl-tRNA synthetase
J Immunol Methods
(1987)
DGI Scott et al.
Response to methotrexate in fibrosing alveolitis associated with connective tissue disease
Thorax
(1980)

IN Targoff et al.

Immunological aspects

CV Dang et al.

Higher eukaryotic aminoacyl-tRNA synthetases in physiologic and pathologic states

Mol Cell Biochem

(1986)

RM Bernstein et al.

Jo-1 and other myositis autoantibodies

IN Targoff et al.

Measurement of antibody to Jo-1 by ELISA and comparison to enzyme inhibitory activity

J Immunol

(1987)

RM Bernstein et al.

Cellular protein and RNA antigens in autoimmune disease

Mol Biol Med

(1984)

IN Targoff et al.

Antibody to threonyl-transfer RNA synthetase in myositis sera

Arthritis Rheum

(1988)

MB Mathews et al.

Myositis autoantibody inhibits histidyl-tRNA synthetase: a model for autoimmunity

Nature

(1983)

MB Mathews et al.

Anti-threonyl-tRNA synthetase, a second myositis-related autoantibody

J Exp Med

(1984)

CC Bunn et al.

Autoantibodies against alanyl-tRNA synthetase and tRNA^ala coexist and are associated with myositis

J Exp Med

(1986)

Targoff IN: Autoantibodies to aminoacyl-transfer RNA synthetases for isoleucine and glycine: two additional synthetases...

M Nishikai et al.

Heterogeneity of precipitating antibodies in polymyositis

S Yoshida et al.

The precipitating antibody to an acidic nuclear protein antigen, the Jo-1, in connective tissue disease

RM Bernstein et al.

Anti-Jo-1 antibody: a marker for myositis with interstitial lung disease

Br Med J

(1984)

MC Hochberg et al.

Antibody to Jo-1 in polymyositis/dermatomyositis: association with interstitial pulmonary disease

J Rheumatol

(1984)

FC Arnett et al.

The Jo-1 antibody system in myositis: relationships to clinical features and HLA

J Rheumatol

(1981)

R Goldstein et al.

Serologic and restriction enzyme studies of HLA-D region genes in myositis

Arthritis Rheum

(1988)

Cited by (116)

Joint and muscle inflammatory disease: A scoping review of the published evidence
2023, Seminars in Arthritis and Rheumatism
Polyarthritis is commonly reported in idiopathic inflammatory myositis patients, but few studies have focused on the overlap of myositis with rheumatoid arthritis which is a difficult diagnosis in the absence of well-defined diagnostic criteria. The primary objective of this scoping review was to map the field of research to explore the potential diagnoses in patients presenting with both myositis and polyarthritis.
Two electronic databases (MEDLINE/PubMed® and Web of Science®) were systematically searched using the terms (myositis OR ‘inflammatory idiopathic myopathies’) AND (polyarthritis OR ‘rheumatoid arthritis’) without any publication date limit.
Among individual records, 280 reports met inclusion criteria after full-text review. There was heterogeneity in the definition of overlap myositis as well as the characteristics of rheumatoid arthritis. In many studies, key data were lacking; rheumatoid factor status was reported in 56.8% (n=151), anti-citrullinated proteins antibodies status in 18.8% (n=50), and presence or absence of bone erosions in 45.1% (n=120) of the studies. Thirteen different diagnoses were found to associate myositis with polyarthritis: antisynthetase syndrome (29.6%, n=83), overlap myositis with rheumatoid arthritis (16.1%, n=45), drug-induced myositis (20.0%, n=56), rheumatoid myositis (7.5%, n=21), inclusion body myositis (1.8%, n=5), overlap with connective tissue disease (20.0%, n=56), and others (5.0%, n=14).
The spectrum of joint and muscle inflammatory diseases encompasses many diagnoses including primitive and secondary myositis associated with RA or arthritis mimicking RA. This review highlights the need for a consensual definition of OM with RA to better individualise this entity from the numerous differential diagnoses.
Pulmonary histopathology of interstitial lung disease associated with antisynthetase antibodies
2022, Respiratory Medicine
We aimed to determine if antibody type is an indicator of pulmonary histopathology, using antisynthetase antibody positive interstitial lung disease (ILD) cases with lung biopsy or autopsy findings.
We conducted a comprehensive review of the English language literature in PubMed to identify ILD histopathology results for cases with antibodies against anti-aminoacyl-transfer RNA (tRNA) synthetases (anti-ARS antibodies), including Jo1, PL-12, PL-7, KS, ES, and OJ. We additionally identified patients who had ILD, anti-ARS antibodies, and a lung biopsy between 2015 and 2020 at Beth Israel Deaconess Medical Center. For each case, we documented the specific anti-ARS antibody and major histopathologic patterns identified on biopsy or autopsy, including usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), organizing pneumonia (OP), and acute lung injury (ALI). To determine if histopathology varied by antibody type, we compared the proportion of each of four major patterns by antibody type using the Fisher's Exact test.
We identified 310 cases with pathology findings and anti-ARS antibody positivity, including 12 cases from our institution. The proportion of NSIP differed significantly across antibody type, found in 31% of Jo1 (p < 0.01), 67% of EJ (p < 0.01), and 63% of KS (p < 0.01) cases. OP was common in Jo1 (23%, p = 0.07), but rare in EJ (4%, p = 0.04) and KS (4%, p = 0.04). UIP was common in PL-12 alone (36%, p = 0.03).
The frequency of histopathologic findings in ILD with anti-ARS positivity varies significantly by antibody type, and NSIP occurs in less than half of all cases.
A 65-year-old Woman With Persistent Dyspnea, Arthritis, and Raynaud's Phenomenon
2021, American Journal of the Medical Sciences
Antisynthetase syndrome (AS) is a rare disease that affects patients with inflammatory myopathies such as polymyositis (PM) and dermatomyositis (DM). In patients with AS, up to 95% of patients develop antisynthetase syndrome-associated interstitial lung disease (AS-ILD). Although AS-ILD commonly occurs in patients with a well-established diagnosis of AS, it can be the first or only manifestation of an occult AS. The frequency of interstitial lung disease (ILD), myopathy, and skin involvement are often dependent on the type of myositis-specific antibodies present. AS-ILD patients who are positive for both anti-Jo-1 and anti-SSA/RO-52 autoantibodies often present with a severe degree of lung restriction on pulmonary function tests and radiologic imaging with an inadequate response toward immunosuppressive therapies. We describe a 65-year-old woman who presents with chronic dyspnea. She was initially diagnosed with corticosteroid-resistant cryptogenic organizing pneumonia based on the radiological findings on her CT chest. Her symptoms did not improve, and she suffered from intolerable corticosteroid-related side effects. Reviews of systems were positive for arthritis and Raynaud's phenomenon. She was found to have elevated inflammatory markers and autoantibodies such as anti-Jo-1, anti-RO-52, and anti-SSA. A diagnosis of AS-ILD resistant to corticosteroid therapy was made. Her lung function improved with combination therapy of mycophenolate and rituximab. Our case highlights that a detailed history and physical exam, compatible radiologic imaging, and autoantibodies are essential for the diagnosis of AS-ILD.
Autoantibodies as biomarkers for interstitial lung disease in idiopathic inflammatory myositis and systemic sclerosis: The case of anti-eIF2B antibodies
2020, Journal of Translational Autoimmunity
Citation Excerpt :
Nevertheless, some patients appear to have idiopathic ILD for years and may not develop myositis. Reports on anti-PL-12 and anti-KS suggested that they are common in ILD without myositis [35–37], as reported also by Kalluri and Colleagues who analyzed the clinical features of 31 anti-PL-12-positive patients and reported that this autoAb is strongly associated with ILD (3/31 cases were idiopathic ILD) but less with myositis and arthritis [38], consistent with an earlier study [35,37]. Marie et al. analyzed 75 anti-Jo-1-positive patients and 20 anti-PL-7 (n = 15)/PL-12-positive (n = 5) patients and reported that the latter had milder muscle involvement, less recurrence of muscle disease and anti-PL-7/PL-12 was associated with early and severe ILD and gastrointestinal manifestations [39,40].
Serum autoantibodies are pivotal for the early detection of systemic autoimmune rheumatic diseases such as Systemic Sclerosis (SSc) and Poly/Dermatomyositis (PM/DM), and in some cases are associated with organ complications such as interstitial lung disease (ILD). A paradigmatic example is provided by the autoantibody against the Eukaryotic Initiation Factor 2B (eIF2B) that has been recently detected in SSc.
Sera from 118 patients with SSc, 8 Poly/Dermatomyositis, 2 overlap SSc/Polymyositis, 4 undifferentiated connective tissue disease-UCTD and 3 healthy controls were tested first by indirect immunofluorescence for anti-nuclear antibodies-ANA pattern. Further, we employed prot
ein-radioimmunoprecipitation (IP) and IP- Western Blot for the detection and confirmation of anti-eIF2B antibodies. Serum findings were further correlated with the clinical features of patients.
We identified 3 SSc cases (2.5%) positive for anti-eIF2B antibodies while this autoantibody was not detected in control sera. Using protein-IP all three patients manifested the 38kD protein which is the antigenic target of anti-eIF2B antibodies, and this was associated with a cytoplasmic pattern at indirect immunofluorescence. The presence of anti-eIF2B was associated with ILD and a diffuse SSc variant, in one case in association with anti-Scl70/topoI.
Our data confirm that a small subgroup (2.5%) of patients with SSc have detectable anti-eIF2B with cytoplasmic-positive staining at immunofluorescence and this reactivity is associated with ILD.
Pulmonary manifestations of antisynthetase syndrome
2015, Revue des Maladies Respiratoires
Le syndrome des antisynthétases correspond à une myopathie inflammatoire fréquemment associée à une atteinte pulmonaire, surtout parenchymateuse (pneumopathie infiltrante diffuse) et plus rarement vasculaire (hypertension pulmonaire). Devant un tableau clinique et radiologique évocateur, la présence d’anticorps anti-ARNt synthétases signe le diagnostic. Les plus fréquents de ces auto-anticorps sont les anti-Jo1, les anti-PL7 et les anti-PL12. De nombreuses manifestations cliniques extrathoraciques associées à l’atteinte pulmonaire peuvent orienter le diagnostic : myalgies ou déficit musculaire, phénomène de Raynaud, polyarthrite, fièvre et « mains de mécaniciens ». Une augmentation des créatine-phospho-kinases est quasi constante. Le recours à l’électromyogramme, à l’imagerie musculaire par résonance magnétique ou à l’histologie n’est pas systématique. Néanmoins, il existe une grande variabilité des symptômes et de leur sévérité d’un patient à l’autre ou au long de l’évolution de la maladie. L’atteinte pulmonaire est un facteur pronostic majeur et incite à traiter de manière intensive les patients, principalement par corticothérapie systémique, voire d’emblée par association corticoïdes et immunosuppresseurs. Mieux connaître cette pathologie qui est souvent de révélation pneumologique permettrait d’améliorer le diagnostic et la prise en charge thérapeutique, voire même le pronostic.
Antisynthetase syndrome is an inflammatory myopathy frequently associated with pulmonary manifestations, especially interstitial lung diseases, and uncommonly pulmonary hypertension. In the context of a suggestive clinical and radiological picture, positive anti-RNA synthetase antibodies confirm the diagnosis. Anti-Jo1, anti-PL7, and anti-PL12 antibodies are the more commonly encountered. The presence of a number of extra-thoracic manifestations in association with pulmonary disease may suggest the diagnosis. These include: myalgia or muscular deficit, Raynaud's phenomenon, polyarthritis, fever, mechanics hands. Serum creatine kinase levels are usually increased. Electromyogram, muscular magnetic resonance imaging or muscle pathology are not mandatory to make the diagnosis. There is a high variability in symptoms and severity, between patients but also during the course of the disease in the same patient. The presence of an interstitial lung disease is a major prognostic factor and an indication for more intensive treatment, principally with systemic corticosteroids with or without immunosuppressive drugs. Improving respiratory physicians’ knowledge of this disease, which is often revealed by its pulmonary manifestations, should help diagnosis, therapeutic management, and possibly prognosis.
Gene-Gene and Gene-Environment Interactions in Defining Risk and Spectrum of Phenotypes in Idiopathic Inflammatory Myopathies
2014, Between the Lines of Genetic Code: Genetic Interactions in Understanding Disease and Complex Phenotypes
The idiopathic inflammatory myopathies (IIMs) represent a complex spectrum of overlapping connective tissue diseases which have skeletal muscle involvement as one of their major components. While recent immunogenetic research has shown that myositis-specific and myositis-associated autoantibodies (MSAs/MAAs) are clearly associated with and thus define many clinical IIM subsets, future research is needed to clarify whether these antibodies (Abs) are just a secondary epiphenomenon, i.e., representing surrogate markers for underlying human leukocyte antigen (HLA) genes and or genotypes, or whether they play some prime role in the immune processes characterizing the IIM. There is increasing evidence suggesting that the IIM disease subtype an individual will get following any environmental triggering event is likely predetermined by their genotype at HLA, and that epistatic genetic interactions in this region critically determine overall disease phenotype, including disease severity and treatment outcomes. It seems clear in inclusion body myositis (IBM), but not yet in other IIM, that HLA gene dosage determines disease severity, again highlighting the importance of epistatic genetic interactions in determining disease characteristics, including outcome. As for rheumatoid arthritis (RA), it appears that HLA genes and the environment interact to modify IIM disease susceptibility. That a specific IIM subtype (necrotizing myopathy characterized by infiltrating macrophages without the usual T and B cells) can be induced in some genetically susceptible individuals by the specific environmental trigger, i.e., the use of certain lipid-lowering statin drugs, suggests that this may represent a potential human model to further study IIM disease-induction mechanisms.

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^☆: This work was supported by Grants AR-32214 and AI-27181 from the National Institutes of Health, by Veterans Administration medical research funds from the Veterans Administration Medical Center, Oklahoma City, Oklahoma, and by grants from the Arthritis Foundation.

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Clinical studiesClinical manifestations in patients with antibody to PL-12 antigen (alanyl-tRNA synthetase)☆

Abstract

Clin Dermatol

J Immunol Methods

Am J Med

J Biol Chem

Am J Med

Thorax

J Rheumatol

J Rheumatol

J Immunol Methods

Thorax

Immunological aspects

Higher eukaryotic aminoacyl-tRNA synthetases in physiologic and pathologic states

Mol Cell Biochem

Jo-1 and other myositis autoantibodies

Measurement of antibody to Jo-1 by ELISA and comparison to enzyme inhibitory activity

J Immunol

Cellular protein and RNA antigens in autoimmune disease

Mol Biol Med

Antibody to threonyl-transfer RNA synthetase in myositis sera

Arthritis Rheum

Myositis autoantibody inhibits histidyl-tRNA synthetase: a model for autoimmunity

Nature

Anti-threonyl-tRNA synthetase, a second myositis-related autoantibody

J Exp Med

Autoantibodies against alanyl-tRNA synthetase and tRNAala coexist and are associated with myositis

J Exp Med

Heterogeneity of precipitating antibodies in polymyositis

The precipitating antibody to an acidic nuclear protein antigen, the Jo-1, in connective tissue disease

Anti-Jo-1 antibody: a marker for myositis with interstitial lung disease

Br Med J

Antibody to Jo-1 in polymyositis/dermatomyositis: association with interstitial pulmonary disease

J Rheumatol

The Jo-1 antibody system in myositis: relationships to clinical features and HLA

J Rheumatol

Serologic and restriction enzyme studies of HLA-D region genes in myositis

Arthritis Rheum

Clinical studies
Clinical manifestations in patients with antibody to PL-12 antigen (alanyl-tRNA synthetase)☆

Autoantibodies against alanyl-tRNA synthetase and tRNA^ala coexist and are associated with myositis