The Pulmonary Histopathology of Anti-KS Transfer RNA
Frank Schneider, MD; Rohit Aggarwal, MD, MS; David Bi, BS; Kevin Gibson, MD; Chester Oddis, MD; Samuel A. Yousem, MD
? Context.—The clinical spectrum of the antisynthetase
syndromes (AS) has been poorly defined, although some
frequently present with pulmonary manifestations. The
anti-KS anti–asparaginyl-transfer RNA synthetase syn-
drome is one in which pulmonary interstitial lung disease
is almost always present and yet the histopathologic
spectrum is not well described.
Objective.—To define the morphologic manifestations
of pulmonary disease in those patients with anti-KS
Design.—We reviewed the connective tissue disorder
registry of the University of Pittsburgh and identified those
patients with anti-KS autoantibodies who presented with
interstitial lung disease and had surgical lung biopsies.
Results.—The 5 patients with anti-KS antisynthetase
syndrome were usually women presenting with dyspnea
and without myositis, but with mechanic’s hands (60%)
and Raynaud phenomenon (40%). They most often
presented with a usual interstitial pneumonia pattern of
fibrosis (80%), with the final patient displaying organizing
Conclusions.—Pulmonary interstitial lung disease is a
common presentation in patients with the anti-KS–anti-
synthetase syndrome, who are often women with rather
subtle or subclinical connective tissue disease, whereas the
literature emphasizes the nonspecific interstitial pneumo-
nia pattern often diagnosed clinically. Usual interstitial
pneumonia and organizing pneumonia patterns of intersti-
tial injury need to be added to this clinical differential
(Arch Pathol Lab Med. 2015;139:122–125; doi: 10.5858/
sitis and polymyositis, in which autoantibodies to specific
aminoacyl–transfer RNA synthetases develop and are
associated with clinical manifestations of myositis, Raynaud
phenomenon, arthritis, fever, mechanic’s hands, and inter-
stitial lung disease (ILD).1–7Anti-Jo1 antihistidyl–transfer
RNA synthetase autoantibodies are found in 20% to 30% of
anti-Jo1 AS, and is the one syndrome most often associated
with pronounced myositis and rash, whereas the other non-
Jo1 antisynthetase syndromes tend to have milder or
subclinical forms of myositis but more significant ILD.1,8
Anti-KS autoantibodies target anti–asparaginyl-transfer
RNA synthetases and occur in 1% to 5% of myositis
patients but often present with pulmonary symptoms
without other clinical manifestations of CTD.9,10Because of
its rarity, its association with ILD has been poorly
recognized.11–13In this paper we report the largest study
to date of the histologic manifestations of ILD in the anti-KS
he antisynthetase syndrome (AS) represents a subset of
connective tissue disease (CTD), usually dermatomyo-
anti–asparaginyl-transfer RNA synthetase syndrome (anti–
MATERIALS AND METHODS
The University of Pittsburgh Connective Tissue Disease Registry
encompasses more than three decades of prospective data and
serum collected on consecutive outpatients and inpatients with
myositis evaluated at the University of Pittsburgh. All variables
(clinical, laboratory, radiographic, and pathologic) as well as organ
system definitions are well defined and standardized in this
registry. The antisynthetase autoantibody–positive group included
patients in the CTD registry who were initially seen between
January 1985 and December 2013 with a positive serum specimen
that may include myositis (polymyositis, dermatomyositis), sys-
temic sclerosa, and undifferentiated CTD, or overlap syndrome.
This study was approved by the Institutional Review Board of the
University of Pittsburgh Medical Center. All patients with the
diagnosis of myositis met the published criteria of Bohan and
Peter.14The diagnoses of systemic sclerosis, undifferentiated CTD,
and overlap syndrome were made clinically by experienced
The prospective CTD registry, combined with a retrospective
review of the electronic medical record for missing data, was used
to summarize the presenting clinical and serologic features,
including CTD diagnosis and organ system involvement. Organ
system definitions are as follows: (1) vascular (presence of Raynaud
phenomenon, digital pitting scars, ulcers and gangrene, or
abnormal nailfold capillaries); (2) cutaneous (dermatomyositis-
specific or associated rashes, or sclerodactyly); (3) joint, based on
objective joint swelling and tenderness; (4) muscle (objective
proximal muscle weakness on manual muscle testing plus any one
of the following: elevated serum creatine kinase, myopathic
electromyogram, or histopathologic myositis on muscle biopsy);
Accepted for publication February 12, 2014.
From the Departments of Pathology (Drs Schneider and Yousem,
Mr Bi), Rheumatology (Drs Aggarwal and Oddis), and Pulmonary
Medicine (Dr Gibson), UPMC Presbyterian, University of Pittsburgh
Medical Center, Pittsburgh, Pennsylvania.
The authors have no relevant financial interest in the products or
companies described in this article.
Corresponding author: Samuel A. Yousem, MD, Department of
Pathology, University of Pittsburgh Medical Center, Presbyterian
Campus – A610, 200 Lothrop St, Pittsburgh, PA 15213-2582 (e-mail:
122Arch Pathol Lab Med—Vol 139, January 2015Anti-KS Interstitial Lung Disease—Schneider et al
(5) gastrointestinal (proximal or distal esophageal dysmotility or
small/large-bowel involvement of systemic sclerosis); and (6)
pulmonary (fibrosis on chest radiograph or high-resolution
computed tomography). Anti-KS antibodies were detected using
a combination of protein and RNA immunoprecipitation in our
Pathology files were searched for all surgical biopsies performed
on patients with anti-KS autoantibodies. Multiple lobes were
sampled in all cases. Hematoxylin-eosin–stained slides were
reviewed, (number range, 4–16; average, 7) and the biopsies were
classified according to the 2002 recommendations of the American
Thoracic Society/European Respiratory Society with regard to the
types of idiopathic interstitial pneumonias.15,16In all cases infection
was excluded by culture studies and/or special histochemical stains,
including Grocott and acid-fast stains.
The clinical characteristics of the 5 patients with anti-KS
AS are shown in Table 1. Four were female and one was
male, with an average age of 49.4 years (range, 40–60 years).
A total of 4 of the 5 patients (80%) presented with dyspnea
as an initial symptom. Only 1 patient presented with clinical
myositis. The most common clinical features were mechan-
ic’s hands (n ¼ 3; 60%) and Raynaud phenomenon (n ¼ 2;
40%). Four patients had radiographic features of usual
interstitial pneumonia (UIP) on high-resolution computer-
ized tomographic scan, with bibasilar reticular infiltrates
with traction bronchiectasis and subpleural honeycomb
change. One patient had radiographic changes suggestive of
nonspecific interstitial pneumonia (NSIP), reflecting bibasi-
lar patchy ground glass infiltrates with subpleural sparing;
however, surgical lung biopsy revealed organizing pneu-
monia (OP) in this case. All patients are alive with persistent
disease (average follow-up time, 79.2 months; range, 36–108
with zones of normal lung and lung with interstitial inflammation was observed (hematoxylin-eosin, original magnification 340).
Usual interstitial pneumonia: at low magnification, a patchwork pattern of honeycomb change with bronchiolar metaplasia associated
patchy chronic inflammation with lymphoid aggregates (hematoxylin-eosin, original magnification 3200).
Usual interstitial pneumonia: temporal heterogeneity of injury was marked by parenchymal eosinophilic scarring, fibroblastic foci, and
(hematoxylin-eosin, original magnification 340).
Organizing pneumonia: an organizing pneumonia pattern was patchy at low magnification, with polyps of airspace granulation tissue
mild alveolar septal mononuclear infiltrate (hematoxylin-eosin, original magnification 3200).
Organizing pneumonia: loose fibromyxoid plugs of granulation tissue with stellate myofibroblasts-filled alveolar ducts and airspaces with
Arch Pathol Lab Med—Vol 139, January 2015Anti-KS Interstitial Lung Disease—Schneider et al123
Surgical lung biopsies were performed on multiple lobes
of lung in all 5 cases, revealing a patten of UIP in 4 and OP
on 1. The 4 cases of UIP showed a temporally heteroge-
neous pattern of subpleural peripheral lobular damage with
areas of honeycomb fibrosis and scarred architecturally
remodeled lung alternating with the zones of septal scarring
and chronic inflammation in a patchwork fashion (Figure 1).
Zones of normal lung were interspersed. At the margins of
these regions of dense scarring, young pauci-inflammatory
fibroblastic foci were identified (Figure 2). Centrilobular/
bronchiolocentric injury was seen in only 1 case, with
interstitial damage largely localized to the subpleural zones
and interlobular septa in most cases. Whereas arteries
showed mild to moderate myointimal thickening, no
evidence of vasculitis was noted. Granulomas and pleuritis
were not seen. One case showed clinical and histologic
features of acute exacerbation/decompensation of UIP in
that the architecturally intact lung contained large numbers
of airspace hyaline membranes. Lymphoid aggregates were
seen in all 5 cases and were found along the lymphatic
routes in the interlobular septa and along bronchovascular
bundles. Respiratory bronchiolitis and emphysema, reflect-
ing smoking-induced lung injury, were noted in 2 instances.
The last case of anti-KS disease demonstrated an OP
pattern, with young granulation tissue plugs filling the
lumens of small airways and tracking down alveolar ducts to
distal airspaces, resulting in cords of branching, arborizing
granulation tissue at low magnification (Figures 3 and 4). A
patchy alveolar septal mononuclear infiltrate with rare
eosinophils was present. Remodeling of the lung parenchy-
ma, scar, and honeycomb change was not observed.
Granulomas and pleuritis were not present.
Anti–aminoacyl-transfer RNA synthetase antibodies are
most often seen in the setting of active myositis.2,5,7,17At
least 8 specificities for these autoantibodies have been
recognized, including anti-Jo1 (anti-histidyl), anti-PL7
(anti-threonyl), anti-PL12 (anti-alanyl), anti-OJ (anti-iso-
leucyl), anti-EJ (anti-glycyl), and anti-KS (anti-asparaginyl).
Whereas anti-Jo1 AS is often accompanied by active
myositis, the non–anti-Jo1 AS syndromes tend to present
with more indistinct clinical features, although they share a
predilection for arthritis, episodic fever, mechanic’s hands,
and ILD.1,18–20In fact, many of these syndromes present
initially with ILD and without myositis, and frequently
patients die of progressive pulmonary failure.1,3,20This
report of 5 cases of ILD due to anti-KS autoantibodies
highlights the need to consider antisynthetase antibodies as
a potential cause of pulmonary fibrosis, and to discourage
simple screening using rheumatoid factor and anti-nuclear
antibodies exclusively to establish an autoimmune etiology.
The study also emphasizes the UIP histopathology in the
anti-KS AS syndrome.
Table 2 reviews the literature summarizing lung biopsy
findings in the anti-KS AS. Interstitial lung disease has been
reported in up to 88% of anti-KS AS.12In contrast to our
study, where 4 patients (80%) revealed a UIP pattern of
fibrosis, only 3 of 7 cases (42%) in the literature noted this
Table 1.Clinicopathologic Characteristics of Patients With Interstitial Lung Disease
Due to Anti-KS/Anti–Asparaginyl-Transfer-RNA Synthetase Syndrome
Abbreviations: ANED, alive, no evidence of disease; AWED, alive with evidence of disease; DM, dermatomyositis; LLL, left lower lobe; LUL, left
upper lobe; NSIP, nonspecific interstitial pneumonia; OP, organizing pneumonia; PM, polymyositis; RA, rheumatoid arthritis; RLL, right lower lobe;
RML, right middle lobe; RUL, right upper lobe; RX, treatment; S&S, signs and symptoms; UCTD, unclassified connective tissue disorder; UIP, usual
interstitial pneumonia; þ indicates present; ?, not present.
Table 2.English Literature Review of Lung Biopsy Histopathologic Changes in Anti-KS Anti–Asparaginyl-Transfer RNA
Hirakata et al,122007
Hirakata et al,122007
Hirakata et al,111999
Hirakata et al,111999
Okayasu et al,132009
‘‘bilateral basilar infiltration’’
‘‘bilateral interstitial fibrosis’’
‘‘bilateral interstitial fibrosis’’
‘‘bilateral ground glass opacity
and consolidation with volume
loss’’...in lower lobes
‘‘subpleural linear opacities in
bilateral lower lobe’’
‘‘peripheral ground glass
opacities, consolidation at
bases; traction bronchiectasis’’
Lost to F/U
Lost to F/U
Lost to F/U
Lost to F/U
ANED (6 mo)
Okayasu et al,132009 57/J/FDOE, coughFibrotic NSIPAWED (11 mo)
Koreeda et al,202010 66/J/F Dyspnea, coughNSIPAWED (32 mo)
Abbreviations: ANED, alive with no evidence of disease; AWED, alive with evidence of disease; CXR/HRCT, chest radiograph/radiograph/high-
resolution chest tomography; DOE, dyspnea on exertion; F/U, follow-up; J, Japanese; NSIP, nonspecific interstitial pneumonia; S&S, signs and
symptoms; UIP, usual interstitial pneumonia.
124Arch Pathol Lab Med—Vol 139, January 2015Anti-KS Interstitial Lung Disease—Schneider et al
pattern.11–13,19Most cases of UIP are cryptogenic and fall
within the idiopathic pulmonary fibrosis category. With our
specific interest in immune-mediated rheumatologic lung
disease, using an expanded panel of autoantibodies that
captures rare specificities often seen in myositis syndromes
may be responsible for our identification of these UIP
pattern cases.5,18Preliminary evidence suggests that early
identification and treatment of ILD in the AS are associated
with a higher response rate to steroids and prolonged life
spans, including patients diagnosed with UIP, and the
average survival time of 79 months in this study supports
this view.1It also appears that non-Jo1 patients have a
worse survival rate compared with Jo-1 patients, and this is
likely related to a higher incidence of pulmonary disease and
the general lack of CTD features, which results in delayed
The morphology of UIP in anti-KS AS displayed no
specific histopathologic features, although lymphoid aggre-
gates were present at a frequency higher than that described
in the literature.5
As has been described, NSIP is commonly seen in patients
with autoimmune disease and comprises 4 of 7 cases (57%)
reported in patients with anti-KS syndrome.11–13We did not
see this pattern in our cases, although within the UIP cases,
focal NSIP patterns were seen in 3 instances. Instead, our
fifth case revealed a heretofore unreported pattern of OP
which is also a common manifestation of ILD in many
autoimmune syndromes, including polymyositis and der-
matomyositis.7Both NSIP and OP may present with ground
glass infiltrates, the former often being more diffuse, but OP
may have a similar pattern if extensive. Still, OP has a
distinctly different histopathology. Like these historic cases,
response to steroids was brisk in this patient.
There are limitations to this study. It is certainly focused
on an unusual rare syndrome that has resulted in scant
comparative literature. Nonetheless, it is likely that a focus
on identifying rare and unusual autoantibodies as part of a
comprehensive patient workup will allow for better sepa-
ration of pulmonary fibrosis subtypes. Second, the study is
retrospective, with most cases being identified after lung
biopsy and a comprehensive autoantibody examination.
Finally, as a referral center for lung transplantation for end-
stage lung disease, we cannot exclude the possibility that
our histopathologic experience has been skewed toward
progressive forms of ILD, especially UIP.
In summary, the anti-KS AS is one of the more subtle
antisynthetase syndromes, with more pronounced respira-
tory complications and often subtle musculoskeletal man-
ifestations. In our experience these patients present with a
UIP pattern of injury, although NSIP and OP represent
other forms of more indolent, potentially steroid-responsive
patterns in patients possessing the anti-KS autoantibody.
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RUL, RML, RLL
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