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Clin Pulm Med. Author manuscript; available in PMC 2017 September 01.
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Clin Pulm Med. 2016 September ; 23(5): 218–226. doi:10.1097/CPM.0000000000000171.

The Diagnosis and Treatment of Antisynthetase Syndrome

Leah J. Witt, MD1, James J. Curran, MD2, and Mary E. Strek, MD1
1Sectionof Pulmonary and Critical Care Medicine, Department of Medicine, The University of
Chicago Medicine, Chicago, IL 60637
2Sectionof Rheumatology, Department of Medicine, The University of Chicago Medicine,
Chicago, IL 60637
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Abstract
Anti-synthetase syndrome is an autoimmune condition, characterized by antibodies directed
against an aminoacycl transfer RNA synthetase along 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 anti-synthetase
syndrome, as compared to dermatomyositis and polymyositis, inflammatory myopathies with
which it may overlap phenotypically. Diagnosis is made by a multidisciplinary approach,
synthesizing rheumatology and pulmonary evaluations, along with serologic, radiographic, and
occasionally muscle and/or lung biopsy results. Patients with anti-synthetase syndrome often
require multi-modality immunosuppressive therapy in order to control the muscle and/or
pulmonary manifestations of their disease. The long-term care of these patients mandates careful
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attention to the adverse effects and complications of chronic immunosuppressive therapy, as well
as disease-related sequelae that can include progressive interstitial lung disease necessitating lung
transplantation, pulmonary hypertension, malignancy and decreased survival. It is hoped that
greater awareness of the clinical features of this syndrome will allow for earlier diagnosis and
appropriate treatment to improve outcomes in patients with anti-synthetase syndrome.

I. Introduction
Anti-synthetase syndrome is an autoimmune disease characterized by autoantibodies against
one of many aminoacyl transfer RNA (tRNA) synthetases with clinical features that may
include interstitial lung disease (ILD), non-erosive arthritis, myositis, Raynaud’s
phenomenon, unexplained fever and/or mechanic’s hands (1). Anti-synthetase syndrome is
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an idiopathic inflammatory myopathy (IIM), with a higher prevalence of ILD compared to

dermatomyositis (DM) and polymyositis (PM), IIMs with which it shares many features.
The ILD in anti-synthetase syndrome patients is often severe and rapidly progressive,
causing much of the increased morbidity and mortality associated with anti-synthetase
syndrome as compared to the other IIMs (2).

Corresponding author: Leah J. Witt, MD (ORCID 0000-0001-5665-4060), leah.witt@uchospitals.edu, The University of Chicago
Medicine, 5841 South Maryland Ave., MC 6076, Chicago, IL 60637, Phone: 608-769-6778, Fax: 773-834-7068.
Conflict of Interest: no authors have conflicts of interest to disclose
 Witt et al. Page 2

Since Bohan and Peter’s 1975 classification of DM and PM, additional research has added
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to our understanding of the heterogeneous phenotypes of patients with IIMs (3, 4). In the
1980s, aminoacyl tRNA synthetase autoantibodies were identified and linked to the IIMs (5,
6). In the early 1990s, several groups recognized that patients with these antibodies had
distinct clinical features, leading to the formal recognition of anti-synthetase syndrome (7,
8). In addition, more subtle forms have been identified, including lung-dominant disease.
Patients with anti-synthetase syndrome have a higher incidence of pulmonary involvement
and symptoms considered to be more characteristic of other connective tissue diseases
(CTDs), such as Raynaud’s phenomenon or gastroesophageal reflux. Patients with anti-
synthetase syndrome may have corticosteroid-resistant myositis or ILD, frequently requiring
additional immunosuppressive medications.

Evidence guiding management of anti-synthetase syndrome is primarily based on case series

and reports. Historically, anti-synthetase syndrome was not considered a separate entity, and
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these patients were diagnosed with either DM or PM depending on their clinical

presentation. Therefore, management decisions in anti-synthetase syndrome are frequently
extrapolated from studies of patients with IIM that included patients with anti-synthetase
syndrome as well. Given the lack of prospective data to guide treatments decisions,
management choices are typically made based on practitioner experience and patient
response to therapy.

This review will summarize the clinical, serologic, and radiographic features of anti-
synthetase syndrome, with particular attention to anti-synthetase syndrome-associated ILD.
We will also review the existing evidence guiding the use of immunosuppressive therapy and
the long-term clinical management of anti-synthetase syndrome.
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II. Diagnosis
Clinical Features
Peter and Bohan’s 1975 criteria for diagnosing DM and PM served for decades as the
framework for the classification of the IIMs (3, 4). Patients were grouped into one of five
classification categories using muscle biopsy, electromyography and serologic data along
with physical examination findings. Since that time, Dalakas and Holhfeld proposed revised
diagnostic criteria in 2003, with a greater emphasis on histologic and immunologic
pathology to distinguish between the IIM subtypes (9).

While Dalakas and Holhfeld’s revised criteria provided clarity for distinguishing between
the IIMs, it was not until 2010 that formal criteria for the diagnosis of anti-synthetase
syndrome were introduced by Connors et al (1). These criteria proposed that all patients with
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anti-synthetase syndrome must have evidence for a tRNA synthetase autoantibody, in

addition to one or more of the following clinical features: mechanic’s hands, Raynaud’s
phenomenon, myositis, ILD, arthritis, and/or unexplained fever (table 1). In 2011, Solomon
et al proposed alternative, stricter criteria, requiring two major or one major and two minor
criteria, in addition to the presence of an aminoacyl-tRNA synthetase autoantibody (10).
Historically, patients with these antibodies were diagnosed with an IIM or were
unrecognized given their atypical clinical features. In fact, in a recent retrospective analysis

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of 198 patients with idiopathic interstitial pneumonia, 13 patients were later noted to have an
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anti-synthetase antibody (11).

The diagnostic criteria proposed by Connors et al and Solomon et al permit recognition of

the anti-synthetase syndrome as a distinct entity, which may be useful in both clinical and
research settings. However, we caution that the absence of an anti-synthetase antibody does
not preclude the presence of the anti-synthetase syndrome because autoantibody levels
fluctuate depending on disease activity (12), centers and laboratories vary in which
autoantibodies they routinely test, and there may be undiscovered autoantibodies not yet
available for laboratory detection. In our experience, we have encountered patients with
clinical features of the anti-synthetase syndrome phenotype along with rapidly progressive
and severe ILD who do not have evidence of anti-synthetase antibodies. While a formal
diagnosis of anti-synthetase syndrome is not possible if an anti-synthetase antibody is not
present, these patients may benefit from pharmacologic therapy as is recommended for
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patients formally diagnosed with anti-synthetase syndrome.

Phenotypically, patients with anti-synthetase syndrome often have signs and symptoms that
overlap with other CTDs, such as Raynaud’s phenomenon, severe gastroesophageal reflux
disease, and non-erosive arthritis. ILD frequently predominates at presentation and
contributes to the high morbidity and mortality in patients with anti-synthetase syndrome.
The prevalence of ILD in anti-synthetase syndrome varies widely and is difficult to
determine as these patients have only recently been studied as a distinct entity from the other
IIMs. In a 2013 study of 203 anti-synthetase syndrome patients, the prevalence of ILD was
86%, more common than the prevalence of myositis (73%) or arthralgia/arthritis (60%) (13).
In fact, anti-synthetase syndrome patients may not have classic myopathic symptoms as is
disease-defining in PM (14), or the myositis may present later in the disease course. We
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carefully examine the hands in patients with ILD as the hyperkeratosis and scaling
characteristic of mechanic’s hands are often subtle findings whose presence should prompt
further testing for anti-synthetase antibodies and elevated muscle enzymes.

Depending on the clinical presentation, additional laboratory testing may help guide the
clinical evaluation of disease extent and organ involvement (15). Myositis activity is
typically assessed via elevations in creatinine kinase (CK) and aldolase. Monitoring these
muscle enzymes in clinically amyopathic patients may uncover subclinical myositis and can
track with muscle disease activity.

Autoantibodies
In patients with IIM, a variety of myositis-specific and associated autoantibodies have been
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described and are frequently tested in the evaluation of idiopathic ILD (16) (tables 2 and 3).
The hallmark of anti-synthetase syndrome is the presence of myositis-specific anti-
synthetase antibodies (table 2). Of the anti-synthetase antibodies, anti-Jo-1, an anti-histidyl-
tRNA synthetase, is most commonly identified. Less common anti-synthetase antibodies
include anti-threonyl (anti-PL7), anti-alanyl (anti-PL12), anti-isoleucyl (anti-OJ), and anti-
gylcyl (anti-EJ) along with others infrequently tested in the clinical setting but reported in
the literature.

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Diagnostic testing for idiopathic ILD also involves other myositis-specific (table 3),
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including those against translational transport (anti-signal recognition particle

autoantibodies), RNA helicase (anti-MDA5 autoantibodies) (17) and nuclear helicase (anti-
Mi-2 autoantibodies (15). Myositis-associated autoantibodies often evaluated include, but
are not limited to, anti-nuclear antibody (ANA), anti-Ro/SSA (18), anti-PM-Scl, anti-Ku,
and anti-U1-RNP (15) (table 3). While anti-Ro/SSA and anti-La/SSB are traditionally
associated with Sjogren’s disease and Sjogren’s-related ILD, anti-Ro/SSA has been
independently associated with anti-synthetase syndrome and more severe and fibrotic ILD
by HRCT (18, 19).

The reported prevalence of autoantibodies in patients with an IIM varies widely. In a 2006
study of 74 patients with IIM, 58% were positive for a myositis-specific autoantibody and
36% had a myositis-associated antibody (with overlap in 20% of patients) (20). In this case
series and others, anti-Jo-1 predominated, and was found to be prevalent in 30% (over half
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of all patients with myositis-specific antibodies were Jo-1 positive). A 2010 Australian study
of patients with anti-synthetase antibodies demonstrated a prevalence of the Jo-1 antibody in
88% of included patients (21). In this study, female patients were more common than male
patients (30:12).

The immunologic pathogenesis of these autoantibodies has not been precisely determined.
Aminoacyl-tRNA synthetases translate proteins from genetically transcribed mRNA. In
1999, Wakasugi and Schimmel identified that these synthetases may act as cytokines,
assisting in cell death and recruitment of inflammatory cells (22). Further studies,
summarized by Ascherman in 2015, have identified innate and adaptive immunity in the
pathogenesis of anti-synthetase syndrome (23).
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The clinical presentation and disease course differs depending on the anti-synthetase
antibody present. Hamaguchi et al reviewed 166 patients with anti-synthetase antibodies,
and demonstrated that patients with anti-Jo-1, anti-EJ, and anti-PL-7 were most often
clinically diagnosed with DM or PM, while patients with anti-PL-12 were most often
clinically diagnosed with amyopathic DM or ILD alone (24). Interstitial lung disease alone
was common in patients with anti-KS and anti-OJ. A 2012 study of the long-term outcomes
of patients with an anti-Jo-1 autoantibody (n=75) and anti-PL7/PL12 autoantibody (n=20)
found that the prevalence of muscle symptoms (weakness and myalgia) was significantly
lower in patients with anti-PL7/PL12 as compared to those with anti-Jo1 (25).

We recommend a high index of suspicion for anti-synthetase syndrome particularly in

patients with idiopathic ILD and/or acute respiratory distress syndrome (ARDS) of unknown
etiology. Anti-synthetase syndrome can present with fever, arthritis, or ILD in isolation.
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Therefore, we encourage physicians to consider this diagnosis in patients with unexplained

acute or chronic interstitial pneumonia, and recommend laboratory evaluation for anti-
synthetase antibodies in patients with otherwise unexplained ILD or acute lung injury.

Radiographic and Histopathologic Features of Anti-synthetase Syndrome

High resolution computed tomography (HRCT) imaging is routine in the work-up and
management of ILD (figures 1 and 2). A 2015 study of the initial and follow-up CT images

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in 26 patients with anti-synthetase syndrome found that traction bronchiectasis, ground glass
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opacities and reticulation are the most common radiographic features at initial diagnosis
(26). The CT patterns most often identified were non-specific interstitial pneumonia (NSIP),
organizing pneumonia (OP) or a combination of the two. At median follow-up of 27 months,
38% of patients had evidence of honeycombing. The presence of NSIP and OP suggests an
underlying autoimmune etiology and in our experience, is not uncommon in anti-synthetase
syndrome (27). High-resolution computed tomography is used to monitor disease activity,
along with history, physical examination, and serologic testing.

Lung biopsy, including transbronchial biopsy, video-assisted thorascopic surgical biopsy and
surgical open lung biopsy, is infrequently performed in patients with anti-synthetase
syndrome as diagnosis is typically made by synthesizing HRCT findings, serologic data,
pulmonary function testing, physical examination and patient symptoms. Studies by Yousem
et al examined the histopathologic findings of patients, using open surgical lung biopsies,
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autopsies and/or native lungs removed for transplantation, with anti-Jo-1 and anti-PL7
antibodies. In 20 patients with anti-Jo-1 antibody, 50% had diffuse alveolar damage and 35%
usual interstitial pneumonia (UIP) on surgical lung biopsy (28) In eight patients with anti-
PL7, lung biopsy showed UIP in half of the patients (29). A 2008 study of transbronchial
biopsy findings in patients with DM/PM and interstitial pneumonia found that patients with
bud-type fibrosis demonstrated increased response to immunosuppressive therapy as well as
survival, as compared to patients with mural incorporation-type fibrosis (30). These studies
taken together suggest that in anti-synthetase syndrome, ILD may be severe, fibrotic, and/or
refractory to therapy.

Myositis is often absent or subclinical in anti-synthetase syndrome, with ILD the primary
clinical manifestation, therefore muscle biopsy is not typically performed. While muscle
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biopsy is useful in the diagnosis of other IIMs (31), there is no evidence regarding the role of
muscle biopsy in the diagnosis of anti-synthetase syndrome.

III. Treatment
Immunosuppressive agents treat the pulmonary and/or muscle manifestations of anti-
synthetase syndrome. Muscle and lung disease may not track together and require separate
monitoring by collaborating rheumatologists and pulmonologists. Corticosteroids have long
been first-line in the treatment of IIMs, though when corticosteroids are used as
monotherapy in anti-synthetase syndrome, there is frequent lung disease recurrence with
corticosteroid tapering. Additional immunosuppressive agents are added for refractory
muscle and/or lung disease and as corticosteroid-sparing agents. Frequently used adjunctive
agents include azathioprine, mycophenolate mofetil, tacrolimus, rituximab, and
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cyclophosphamide, though there is little consensus about which agent is preferred, and the
use of these agents to treat anti-synthetase syndrome related ILD is off-label (table 4). When
muscle and/or lung disease symptoms stabilize, providers typically slowly taper
corticosteroids, in order to spare patients the long-term side effects. There is no evidence to
guide providers about the length of immunosuppressive therapy, rate of medication tapering
or the consequences of withdrawal even after a patient has entered a clinical remission. In
the experience of this review’s rheumatologist (JC), CK may never completely normalize in

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some African American patients. This is in line with previously published data that African-
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American patients often have higher mean CK levels (32).

Careful laboratory and clinical evaluation is imperative for patients treated with
immunosuppressive agents. Prescribing providers should be familiar with evidence-based
immunosuppressive clinical guidelines (33, 34). The aforementioned medications suppress
normal immune function in an effort to combat aberrant pathogenic autoimmunity. An
unintended consequence for patients treated with all of these immunosuppressive agents is
the increased risk of opportunistic infections and malignancy, particularly skin cancer and
lymphoma. If patients are to be treated with corticosteroids and an additional
immunosuppressive agent, we recommend pneumocystis jiroveci prophylaxis (35).

Adherence to evidence-based vaccination recommendations is also necessary, though many

immunosuppressive agents preclude administration of live vaccinations. Additionally,
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hepatitis B reactivation is common (up to 40%) in patients who are hepatitis B surface
antigen positive and are treated with immunosuppressive agents (36). Hepatitis B surface
antigen, anti-hepatitis B core antigen and hepatitis C antibody should be performed prior to
administration of prednisone or other immunosuppressive therapy. Guidelines recommend
prophylactic antiviral therapy in patients at risk for hepatitis B reactivation. Patients with
positive hepatitis serologies should be treated in consultation with a liver specialist.

We recommend a multidisciplinary approach to care for these patients, with close

collaboration between rheumatologists and pulmonologists. Careful titration of chosen
agents, while monitoring disease status and organ function, allows the safe administration of
these medications, by practitioners experienced with their use. As noted previously, most
data supporting the use of the following agents in anti-synthetase syndrome is extrapolated
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from studies on DM and PM.

Corticosteroids
Since the first administration of “Compound E” in 1948, which would later be renamed
“cortisone”, to treat rheumatoid arthritis, corticosteroids have become nearly ubiquitous in
the management of autoimmune conditions (37). Corticosteroids have wide ranging
mechanisms of action in their role as analogs of adrenal cortex innate functions. In this
context, corticosteroids are prescribed for their anti-inflammatory, immunosuppressive, and
anti-proliferative effects. They are the initial therapy given to treat active muscle and/or lung
disease in patients with an IIM, with or without lung involvement (38).

Controlled trials have not been performed to establish the superiority of corticosteroids in
the initial management of active disease, as compared to other immunosuppressive agents. A
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1993 study of 113 patients with an IIM compared the efficacy of prednisone, methotrexate
and azathioprine by clinical and autoantibody groups (38). Clinical response was mostly
judged by myositis symptoms, not by lung disease symptoms. The first trial of prednisone
alone for 4 weeks resulted in a partial improvement in most patients with anti-synthetase
antibodies, but complete clinical response was rare. Given these findings, patients with anti-
synthetase syndrome may require multimodality therapy at the outset, with frequent
monitoring of lung function.

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Adverse events in patients treated with corticosteroids long-term are frequent, and include
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hyperglycemia, hypertension, weight gain, adrenal suppression, osteoporosis and fractures,

among many others (39). Patients should be monitored closely, and corticosteroids should be
tapered when clinically indicated.

Azathioprine
Azathioprine decreases immune function by halting purine synthesis and incorporating
metabolites into DNA, thus stopping replication particularly of immune cells. Azathioprine
is frequently used as adjunctive therapy in patients with IIM-ILD, particularly in patients
with corticosteroid-resistant disease. While there is little evidence demonstrating
azathioprine’s superiority as the preferred corticosteroid-sparing immunosuppressive agent,
azathioprine has been most frequently used as maintenance therapy often in conjunction
with prednisone (40).
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Evidence to support azathioprine’s efficacy in treatment of anti-synthetase syndrome-ILD is

largely driven by studies in patients with IIM with myositis-predominant symptoms. A 1980
prospective, randomized controlled trial studied the use of azathioprine in PM in 16 patients,
treated either with prednisone plus placebo or prednisone plus azathioprine (41). This study
demonstrated no significant difference in muscle strength or CK level after three months. A
follow-up study in this same group of patients demonstrated that at one year, the prednisone/
azathioprine group required significantly less prednisone than the prednisone only group for
myositis control and this group also had significant improvement in functional disability
(42). A major limitation of this data is that it did not assess for the presence of ILD or ILD
response to therapy.

Patients receiving azathioprine should have their complete blood count and renal/liver
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function monitored every 1–3 months (33). Adverse reactions to azathioprine include
nausea, pancreatitis, hepatitis, and cytopenias. Rarely, an acute febrile hypersensitivity
reaction can occur.

Mycophenolate mofetil
Mycophenolate mofetil inhibits proliferating lymphocytes by altering purine synthesis. It is
used in post-transplant anti-rejection regimens and is also frequently used in the treatment of
CTD. Swigris et al demonstrated its safety and efficacy in a heterogeneous group of patients
with CTD-ILD in 2006. This case series assessed 28 patients treated with MMF for nearly
36 patient-years (43). All but two patients tolerated the medication and its use resulted in a
significantly lower dose of corticosteroids. A 2013 study by Fischer et al demonstrated
similar tolerability of mycophenolate mofetil in 125 patients with CTD-ILD (44). In this
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study, mycophenolate mofetil treatment was associated with stable or improved lung
function over several years of follow-up. A subset of patients with IIM-ILD showed
improved lung function with mycophenolate mofetil.

Common adverse effects include nausea, diarrhea/colitis, hypertension, hyperglycemia and

cytopenias, among many more. Persistent or severe diarrhea may be a sign of serious colitis,
and if it persists warrants further evaluation. Enteric-coated mycophenolic acid is an
alternative to mycophenolate mofetil, as it has been demonstrated to have fewer

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gastrointestinal side effects with similar medication efficacy (45). Providers should monitor
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complete blood counts every 1–3 months and consider monitoring drug clearance if signs of
intolerance occur (33).

Calcineurin Inhibitors: Tacrolimus and Cyclosporine

The calcineurin inhibitors tacrolimus and cyclosporine exert their anti-immune effects via
inhibition of T cells. Tacrolimus has both greater potency and an improved safety profile
when compared to cyclosporine (46), so may be the preferred calcineurin inhibitor in anti-
synthetase syndrome-ILD. To the extent that the IIMs may be T-cell driven in their
pathogenesis, these drugs are the logical choice as an adjunctive therapeutic agent.

A 2013 study of 18 patients with anti-Jo-1 antibodies (17 with ILD) who received
cyclosporine after failing prednisone, revealed that these patients had a statistically
significant improvement in forced vital capacity (FVC) and diffusing capacity for carbon
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monoxide (DLCO), without any life-threatening complications at one year of follow-up

(47). Four patients stopped cyclosporine and experienced a relapse in ILD. Re-treatment
with cyclosporine resulted in improvement in two patients.

The first successful use of tacrolimus was reported in 1999 by Chester Odis, in 8 patients
with PM-ILD (48). Six of these patients had anti-Jo-1 and two had anti-SRP autoantibodies.
Since that time, numerous case reports and studies have suggested the efficacy of tacrolimus
in patients with CTD and IIM related ILD (49), even as add-on therapy in combination with
corticosteroids and an additional immunosuppressive agent (50). A 2005 case series
specifically studied tacrolimus efficacy in 15 patients with anti-synthetase syndrome-ILD.
Most of these patients had Jo-1 autoantibodies, and experienced improvement in lung
function and muscle symptoms, as well as a significant reduction in corticosteroid dose, with
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tacrolimus administration (51).

Providers should closely monitor calcineurin inhibitor serum trough levels, particularly with
dosage changes, worsening myositis or ILD, or with fluctuating renal clearance. It is our
practice to initiate tacrolimus at 1mg twice daily, and increase by 1–2 mg weekly until 12
hour target trough levels reach 5–8 ng/mL (50). Final doses are typically 1 mg to 5 mg,
twice daily. Providers should closely follow blood pressure, renal function, electrolytes,
lipids, and complete blood count (33). Adverse events in patients treated with tacrolimus
include renal dysfunction, hyperkalemia, hyperylcemia, hypertension, tremor, and headache.
If used as add-on therapy in addition to another immunosuppressive agent, we advocate that
tacrolimus should be the first agent to stop after prednisone once a patient has entered a
clinical remission, given the risk of renal dysfunction with the long-term use of tacrolimus.
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Rituximab
Rituximab is a monoclonal antibody that targets the CD20 surface antigen on B-
lymphocytes. Oddis et al performed the largest randomized placebo-controlled trial of
rituximab treatment for refractory adult and juvenile DM and adult PM in 2012 (52). In this
delayed-start study, 195 patients received rituximab plus non-standardized
immunosuppression either at week 1 or at week 8 with total follow-up of 44 weeks. There
was no difference in time to myositis disease control between the groups, though 83% of

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patients achieved the predefined clinical response by the end of the study. This study did not
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look at the presence of ILD or its response to this therapy.

Two small case series have suggested efficacy in patients with ILD due to either CTD or
anti-synthetase syndrome. A 2009 case series described 11 patients with anti-synthetase
syndrome-ILD and declining lung function who were treated with rituximab (53). At short-
term follow-up (approximately 7 months) six of eleven patients had an improvement of over
10% in FVC. One patient died of pneumocystis jiroveci pneumonia, a complication of
chronic immunosuppression.

In 2012, rituximab was proposed as “rescue therapy” in a case series of eight patients with
severe ILD due to CTD (54). Four of these patients had an anti-Jo-1 antibody with HRCT
suggestive of fibrotic NSIP. All of the patients included had a decline in lung function before
rituximab initiation, and at follow-up 9–12 months later showed improvement in pulmonary
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symptoms and/or lung function. A 2014 follow-up study by the same authors of 50 patients
with ILD (5% with IIM) treated with rituximab again suggested efficacy (55).

Common side effects of rituximab include headache, nausea and vomiting, diarrhea and
infection (52). Other serious adverse events include cytopenias and fatal infusion reactions.
Providers should ensure that patients do not have viral hepatitis before choosing rituximab,
and should monitor complete blood counts before every rituximab infusion (33).

Cyclophosphamide
Cyclophosphamide is an anti-proliferative cytotoxic agent that alkylates DNA. Given the
serious nature of many of the potential adverse effects associated with its use, it is typically
reserved for the treatment of severe IIM-ILD, particularly the acute respiratory distress
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syndrome. Its efficacy in treating IIM with and without ILD has been demonstrated in
several case series. A 2015 systematic review analyzed the findings of 12 studies performed
between 1975 and 2014, in which 178 patients with an IIM and 141 patients with IIM-ILD
were treated with cyclophosphamide (56). With the caveat that the dosages of
cyclophosphamide varied as did the co-administered immunosuppressants, approximately
71% demonstrated improvement in vital capacity or FVC and 69% had improved DLCO.
The most common side effects were nausea and vomiting. Several patients had evidence of
opportunistic infections. Two of the most feared complications of cyclophosphamide,
malignancy and hemorrhagic cystitis, were not observed.

A 2013 review of 42 patients with PM/DM-ILD compared outcomes in patients treated with
either cyclophosphamide, azathioprine or mycophenolate mofetil (57). No significant
difference in lung function was demonstrated, though six patients were switched to another
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agent from cyclophosphamide after six months in an attempt to avoid toxic side effects.

Concerns over the cytotoxic effects of cyclophosphamide often limit its administration to
severe and refractory anti-synthetase syndrome-ILD. The use of cyclophosphamide has been
linked to many different malignancies. It has also been associated with sterility, hemorrhagic
cystitis, congestive heart failure, cytopenias, and opportunistic infections.
Cyclophosphamide should be prescribed only by providers familiar with its adverse effects

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and need for frequent monitoring. Patients should have complete blood counts, renal
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function, and urinalysis prior to every administration of cyclophosphamide (usually every 1–

2 weeks) (33).

Other therapies
Intravenous immunoglobulin (IVIG), a blood product containing the pooled
immunoglobulin G antibodies from donors, is used in the treatment of many immune
deficiency and autoimmune disorders, though its exact mechanism of action is unknown. In
a randomized, placebo controlled trial of IVIG treatment in 15 patients with
dermatomyositis, patients randomized to receive IVIG had significant improvement in
muscle strength and symptoms (58). A recent case report suggested IVIG may be effective
in ILD related to IIM as well (59). It is typically used as adjunctive therapy.

Finally, despite methotrexate’s demonstrated efficacy in IIM, methotrexate is typically

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avoided in patients with ILD due to its link to drug-induced pneumonitis (60). Methotrexate
has demonstrated utility in active myositis and is considered first line therapy in IIM patients
without ILD, therefore methotrexate may be required in refractory muscle disease. Its use in
patients with ILD necessitates careful pulmonary monitoring.

IV. Co-morbidities and Survival

Pulmonary Hypertension
Patients with ILD are at additional risk for developing pulmonary hypertension (PH), as
compared to IIM patients without ILD, which causes increased morbidity and mortality. In a
2013 study of 203 anti-synthetase syndrome patients with ILD and/or myositis/arthritis
symptoms, 23.2% had a transthoracic echocardiogram suggestive of pulmonary hypertension
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(13). Of the 47 patients suspected of PH, 45% had a right heart catheterization performed
following the echocardiogram, which confirmed pulmonary hypertension in 7.9% of the
total study population. All 16 patients with confirmed PH had ILD. Survival in patients with
PH and ILD was significantly lower than in patients with ILD who did not have PH.

Malignancy
Dermatomyositis has long been associated with increased risk of malignancy, however there
is little evidence to guide the evaluation for malignancy in patients with anti-synthetase
syndrome. The first case report of cancer-associated anti-synthetase syndrome was in 2008,
in a 59 year old patients with colon adenocarcinoma (61). Several case reports and series
have followed, with widely varying prevalence rates, up to approximately 14% (19, 62, 63)
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In a larger retrospective analysis of 233 patients with anti-synthetase syndrome, the

frequency of cancer was only 1.7% within three years from anti-synthetase syndrome
diagnosis, which the authors assert was not much different than the general population in
France (64). These studies suggest that care providers of these patients should follow age-
appropriate cancer screening, but there is no evidence to guide additional or non-guideline
based evaluation. Interestingly, treatment of the underlying malignancy has been

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 Witt et al. Page 11

demonstrated in case reports to improve myositis and ILD (65), further suggesting that IIM
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can be a paraneoplastic syndrome.

Survival
Several studies suggest that patients with anti-PL7/PL12 autoantibodies have aggressive ILD
and decreased survival as compared to those with anti-Jo-1 autoantibodies. Additionally,
patients with other anti-synthetase antibodies may not be appropriately diagnosed, which
may slow the institution of therapy. One retrospective review found a 0.6 year median delay
to diagnosis in patients with a non-Jo-1 anti-synthetase antibodies compared to patients with
a Jo-1 antibody (66). In an analysis of patients with anti-synthetase syndrome, decreased
survival was seen in patients without muscle weakness and with severe dyspnea (64).
Patients with anti-PL7 or anti-PL12 often have severe and difficult to treat ILD, frequently
without myositis (67), suggesting that the pulmonary manifestations of anti-synthetase
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syndrome are responsible for the difference in mortality. These findings were reproduced in
a 2014 meta-analysis of 27 studies on anti-synthetase syndrome, in which the authors found
that arthralgia and ILD predominate in anti-synthetase syndrome as compared to the other
IIMs, and patients with Jo-1 have more myositis and a better prognosis compared to PL7 and
PL12 (68).

In a 2015 survival analysis of 45 patients with anti-synthetase syndrome-ILD, 14% of

patients had died at 5 years (69). Survivors more frequently had Jo-1 positivity and arthritis.
Patients who died had a significantly lower baseline FVC and more patients that could not
perform DLCO due to severity of disease. A 2013 retrospective evaluation of 202 patients,
with an anti-synthetase antibody from the University of Pittsburgh CTD Registry during a 24
year time period, found a 5-year cumulative survival of 90% for Jo-1 patients and 75% for
non-Jo-1 patients (66). The 10-year survival was 70% for Jo-1 patients and 49% for non-
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Jo-1 patients. The most common causes of death were pulmonary fibrosis and pulmonary
hypertension. Of this cohort, 6% underwent lung transplantation. As patients with ILD due
to anti-synthetase syndrome often have severe and aggressive ILD requiring multi-modality
therapy, physicians should consider early referral to centers capable of lung transplantation
when disease progresses or fails to adequately respond to treatment.

V. Conclusion
Anti-synthetase syndrome, characterized by the presence of an anti-tRNA synthetase
antibody along with a distinct phenotype that includes a high burden of ILD, is an
increasingly recognized clinical entity within the IIMs. Interstitial lung disease associated
with anti-synthetase syndrome is often more severe and rapidly progressive when compared
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to other IIMs, which contributes to the increased morbidity and mortality seen in anti-
synthetase syndrome (table 5).

Diagnosis is undertaken via a comprehensive history and physical examination focused on

CTD signs and symptoms that include Raynaud’s phenomenon, mechanic’s hands,
unexplained fever, myositis and non-erosive arthritis. HRCT imaging along with pulmonary
function testing is crucial in screening for and characterizing the extent of pulmonary

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 Witt et al. Page 12

involvement. Muscle and lung biopsies are infrequently required for diagnosis, but can aid in
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understanding severity of disease and the likelihood of response to therapy.

Immunosuppressive agents, such as azathioprine, mycophenolate mofetil, and/or tacrolimus,

are usually required in addition to corticosteroids for management of the myositis and
pulmonary manifestations of anti-synthetase syndrome. No study has demonstrated the
superiority of a particular agent, so the choice of therapy is guided by practitioner comfort
and a careful assessment of potential risks of therapy in an individual patient. Our practice is
to initiate prednisone and azathioprine or mycophenolate mofetil in patients with anti-
synthetase syndrome related ILD, with the addition of tacrolimus for rapid disease control in
more severe ILD (50). In the setting of anti-synthetase syndrome, we use rituximab for
patients with severe progressive and/or refractory ILD and have used cyclophosphamide in
ARDS.
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In addition to monitoring ILD and myositis, providers should carefully attend to other co-
morbidities associated with anti-synthetase syndrome, including pulmonary hypertension
and screen for malignancy. Survival is decreased in patients with anti-synthetase syndrome-
ILD as compared to patients with an IIM in general. Survival also appears to vary in anti-
synthetase syndrome depending on the autoantibody present, with Jo-1 having the best
prognosis. Referral to tertiary care centers capable of lung transplantation should be
considered in patients with severe and/or rapidly progressive ILD.

Evidence guiding management decisions is limited, and is primarily based on case reports
and series. Prospective studies are urgently needed to guide treatment choices and determine
which immunosuppressive agents offer control of disease and improved survival. It is also
imperative that studies examine the rate of relapse when these therapies are withdrawn, so as
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to guide the length of therapy.

Acknowledgments
Funding: Funding support is provided by the NIH funded Research Training in Respiratory Biology grant at the
University of Chicago (T32 HL007605).

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Figure 1. High-resolution CT in anti-synthetase syndrome at presentation

48 year-old woman with Jo-1 positive anti-synthetase antibody syndrome, presented with
acute respiratory distress syndrome. HRCT reveals bilateral, diffuse groundglass opacities.
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Figure 2. High-resolution CT anti-synthetase syndrome after treatment

The same patient eleven days after treatment with IV cyclophosphamide and high-dose
corticosteroids. Tacrolimus was also initiated. The cyclophosphamide was subsequently
switched to azathioprine after discharge from the hospital. Lung function normalized despite
tapering off prednisone. Lung disease relapsed when patient self-discontinued tacrolimus.
She is now back in remission on a prednisone taper, azathioprine and tacrolimus.
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Table 1

Proposed Diagnostic Criteria for Anti-synthetase Syndrome

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Connors et al. (2010) (1) Solomon et al (2011) (10)

Required: Presence of an anti-aminoacyl tRNA synthetase Required: Presence of anti-aminoacyl tRNA synthetase antibody
antibody
PLUS one or more of the following clinical features: PLUS two major or one major and two minor criteria:
Major:
• Raynaud’s phenomenon
1 Interstitial Lung Disease (not attributable to
• Arthritis another cause)
• Interstitial lung disease 2 Polymyositis or dermatomyositis by Bohan and
Peter critieria
• Fever (not attributable to another cause)
Minor:
• Mechanic’s hands (thickened and cracked
skin on hands, particularly at fingertips) 1 Arthritis
2 Raynaud’s phenomenon
Mechanic’s hands
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3
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Table 2

Anti-synthetase Antibodies
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Anti-ARS antibodies Auto-antigen Clinical features

Anti-Jo1* histidyl Most common

Anti-PL7* theronyl Severe ILD

Anti-PL12* alanyl Severe ILD

Anti-OJ* isoleucyl

Anti-EJ* glycyl

Anti-KS asparaginyl

Anti-Zo phenylalanyl

Anti-SC lysyl

Anti-JS glutaminyl
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Anti-YRS tyrosyl

ILD = Interstitial lung disease

*
available for testing at our institution
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Table 3

Myositis Specific and Associated Antibodies

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Myositis-specific
Anti-SRP

Anti-MDA-5

Anti-Mi-2

Myositis-associated
ANA

Anti-Ro/SSA

Anti-PM-Scl

Anti-KU

Anti-U2 snRNP
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Table 4

Therapies for Anti-synthetase Syndrome-ILD

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Drug Suggested Starting Dose Clinical Use Monitoring Adverse effects*

Corticosteroids 1 mg/kg/day First-line therapy Glucose, weight, blood Hypertension, weight
pressure gain, hyperglycemia

Azathioprine 1 mg/kg/day Most common second- CBC, renal/liver function Leukopenia, hepatic
line agent injury, pancreatitis

Mycophenolate mofetil 500 mg twice daily Second-line agent in CBC Diarrhea, cytopenias
addition to
corticosteroids

Tacrolimus 1 mg twice daily Add-on therapy Renal function, blood Renal failure,
pressure, electrolytes, CBC, hypertension,
drug level hyperglycemia

Rituximab ** Rescue therapy, added CBC Infection, neutropenia,

to standard infusion reaction
immunosuppression
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Cyclophosphamide 1–2 mg/kg/day by mouth or Rescue therapy (e.g. CBC, urinalysis, renal Malignancy, cytopenias,
500–1000 mg IV every 4 ARDS) function hemorrhagic cystitis,
weeks** sterility

IVIG ** Add-on therapy Immunoglobulin G levels Infusion reaction,

infection from donor

ILD = Interstitial lung disease; ARDS = acute respiratory distress syndrome; IVIG = intravenous immunoglobulin G; mg = milligram; kg =
kilogram
*
all except IVIG increase the risk of opportunistic infection
**
rheumatology consult strongly advised
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Clin Pulm Med. Author manuscript; available in PMC 2017 September 01.
 Witt et al. Page 23

Table 5

Clinical Pearls in Anti-synthetase Syndrome

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• Suspect if unexplained acute respiratory distress syndrome, idiopathic interstitial lung disease (particularly NSIP and/or
OP), Raynaud’s phenomenon, fever, and/or mechanic’s hands
• Anti-Jo-1, anti-PL 7, and anti-PL 12 are the most frequently noted anti-synthetase antibodies; ANA and anti-Ro/SSA
may suggest myositis-related ILD
• Has severe and aggressive ILD as compared to the other idiopathic inflammatory myopathies
• Often requires multi-modality immunosuppression
• First-line therapy is prednisone AND mycophenolate mofetil or azathioprine; consider tacrolimus as add-on therapy
• Monitor pulmonary function tests every 2–3 months unless in remission
• If ILD progresses despite therapy, refer for lung transplant evaluation

NSIP = non-specific interstitial pneumonia; OP = organizing pneumonia; ILD = interstitial lung disease; ANA = anti-nuclear antibody
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