Seminars in Arthritis and Rheumatism 51 (2021) 72 83

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Seminars in Arthritis and Rheumatism

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Antisynthetase syndrome much more than just a myopathy

Aleksandra Halina Opinc, Joanna Samanta Makowska*

d
z, Poland
Department of Rheumatology, Medical University of Lodz, ul. Pieniny 30, 92-115 ºo

A R T I C L E I N F O A B S T R A C T

Keywords: The aim of the study was to summarize current knowledge on antisynthetase syndrome (ASS), including its
Antisynthetase syndrome epidemiology, pathogenesis, proposed so far diagnostic criteria, heterogeneity of clinical manifestations,
Antisynthetase antibodies prognostic factors and therapeutic possibilities. PubMed database was screened for “antisynthetase syn-
Idiopathic inflammatory myopathy drome” OR “antisynthetase antibodies” between February and April 2020. Aminoacyl-tRNA synthetases par-
Myositis
ticipate in the immune system activation as antigens, but also serve chemoattractive and cytokine-
Arthritis
resembling roles, initiating innate and adaptive pathways. Exposure to various inhaled antigens may induce
Interstitial lung disease
the autoimmune cascade leading to ASS. NK cells with its impaired INF-y production as well as formation of
NETs by neutrophils contribute to pathogenesis. The prevalence of symptoms vary significantly depending
on the study with muscular, articular and pulmonary involvement being the most frequently observed.
Although classified as subtype of idiopathic inflammatory myopathies, myositis may not necessarily be the
prominent manifestation. Since clinical presentation is heterogeneous and symptoms can emerge gradually,
ASS could be considered as a heterogeneous spectrum rather than a homogenous disease entity. The cur-
rently available classification criteria do not fully correspond with the clinical patterns of the disease. Ther-
apy is based on glucocorticosteroids and other immunosuppressive agents. Randomized controlled trials,
dedicated for patients with ASS, are needed to form treatment algorithms.
© 2020 Elsevier Inc. All rights reserved.

Introduction
Antisynthetase syndrome (ASS) is defined as a subtype of idio-
pathic inflammatory myopathies (IIMs), however, its clinical presen-
tation extends far beyond muscles. Frequent pulmonary
involvement, arthritis, an exceptional pattern in muscle biopsy, fever
of unknown origin, typical cutaneous lesions and Raynaud’s phenom-
enon cover the unique spectrum with aminoacyl-tRNA-synthetases
being both the hallmark and the trigger. The aim of this review is to
summarize current knowledge on this rare disease, to highlight the
heterogeneity of clinical presentation and to propose a novel
approach to patients with ASS symptoms.
Review methodology
PubMed database was screened for “antisynthetase syndrome” OR
“antisynthetase antibodies” between February and April 2020. Pub-
lished, original studies were considered. As there is little relevant
data on this topic, the authors did not limit the literature search to
certain years of publication, however, priority was given to studies
conducted between 2015 and 2020. Articles in languages other than
* Corresponding author at: Department of Rheumatology, Medical University of

d
z, Poland.
Lodz, ul. Pieniny 30, 92-115 ºo
E-mail address: joanna.makowska@umed.lodz.pl (J.S. Makowska).
English were excluded. Abstracts and full articles were read, relevant
studies were incorporated.
Epidemiology
Although first incidences of ASS were described over 30 years
ago [1], the prevalence and pathogenesis remain not fully recog-
nized. First description of ASS is owned to Hochberg et al., who
not only noted high prevalence of anti-Jo-1 antibodies in patients
with PM (polymyositis) or PM-overlapping syndrome but also
reported for the first time the association between anti-Jo-1 and
interstitial lung disease [1]. Few years later, the spectrum of
symptoms such as myositis, pulmonary fibrosis, arthritis, sclero-
dactyly, Raynaud’s phenomenon, dry eyes, hepatitis and calcinosis
in 29 patients with anti-synthetase antibodies was described by
Marguerie [2]. According to Orphanet, global prevalence of ASS is
estimated as 1 9/100 000 [3], however, no precise data on the
disease incidence is available. Antisynthetase antibodies can be
found in 11.1 39.19% of patients with IIM [4 10]. According to
the EuroMyositis registry, ASS is less prevalent than DM (derma-
tomyositis) and PM (polymyositis), but more frequent than sIBM
(sporadic inclusion body myositis) and IMNM (immune-mediated
necrotizing myopathy). Like other IIM subtypes apart from sIBM,
ASS more frequently affects females (female to male ratio is esti-
mated to be approximately 7:3). Mean age at the onset of the

https://doi.org/10.1016/j.semarthrit.2020.09.020
0049-0172/© 2020 Elsevier Inc. All rights reserved.
 A.H. Opinc and J.S. Makowska / Seminars in Arthritis and Rheumatism 51 (2021) 72 83
disease is 48§15 years, which is similar to DM and PM patients
but younger than in sIBM and IMNM [8].
Pathogenesis
Anti-synthetase antibodies (ARS) are directed against cytoplasmic
aminoacyl-tRNA synthetases that catalyse the ATP-dependant reac-
tion of single amino acid attachment to its specific tRNA and ensure
the proper protein synthesis. Although 20 amino acids can be distin-
guished, antibodies have been detected against eight of them, includ-
ing anti-Jo-1 (histidyl-tRNA synthetase), anti-PL-7 (threonyl), anti-
PL-12 (alanyl), anti-EJ (glycyl), anti-OJ (isoleucyl), anti-KS (aspara-
ginyl), anti-Zo (phenylalanyl) and anti-Ha (tyrosyl) [11,12]. ARS can
be found in approximately 30% of IIM with anti-Jo-1 being the most
common type. Anti-Jo-1 specificity is detected in approximately
20 30% myositis patients, while each of the other ARS occurs in not
more than 5% of patients [13]. ARS are generally considered to be
mutually exclusive [12], yet cases of ARS co-occurrence have been
described [14]. Antibodies against Ro (including Ro52) are considered
as the most common type of associated antibodies in ARS-positive
patients, occurring in 30 65% of cases [15,16].
Apart from its basic function, aminoacyl-tRNA synthetases play an
important role in different immune processes. As extracellular sig-
nals, aminoacyl-tRNA synthetases are capable of targeting versatile
immune cells, endothelial cells, fibroblasts and also cancer cells [17].
Those enzymes participate in the immune system activation as anti-
gens, serve chemoattractive and cytokine-resembling roles. By initi-
ating of innate and adaptive pathways, they impose immune
tolerance, breakdown or tissue damage [18,19]. Histydyl-tRNA syn-
thetase (HisRS) and asparaginyl-tRNA synthetase have been found to
regulate the migration of lymphocytes, activation of monocytes and
immature dendritic cells. Histydyl-tRNA synthetase also induced
migration of CCR5-transfected HEK-293 cells while asparaginyl-tRNA
and seryl-tRNA synthetases stimulated migration of CCR3-trans-
fected cells [20]. Depending on the subtype, aminoacyl-tRNA synthe-
tases can impose angiostatic or angiogenic effect. Some of the
synthetases may promote apoptosis of cancer cells [17]. In murine
models, immunization with intact or cleaved HisRS leads to forma-
tion of autoreactive B cells [21]. IgG fraction of sera of anti-Jo-1 posi-
tive patients were also observed to induce IFN-a production [22].
HisRS was found to be overexpressed in immune cells that infil-
trate inflamed and regenerating myofibers of patients with IIM, but
also in the normal lung tissue [23,24]. Two different conformations of
HisRS have been distinguished based on their susceptibility to gran-
zyme B cleavage and modification by autoantibody binding. The iso-
form sensitive to granzyme-B cleavage was found to be highly
expressed in the alveolar epithelium [25].
Antibodies against aminoacylo-tRNA are typically assessed in the
serum, yet the presence of antibodies against HisRS (anti-Jo-1) was
recently detected also in BALF (bronchoalveolar lavage fluid) [26],
which supports the hypothesis of the respiratory tract as the place
where the cleavage of aminoacylo-tRNA is initiated, leading to activa-
tion of T cells that acquire a pro-inflammatory phenotype with subse-
quent stimulation of B cells to maturate and produce anti-Jo-1
antibodies. Since the release of granzyme B may be triggered by envi-
ronmental factors such as pathogens or smoking, hypothesis of envi-
ronmental factors initiating immune dysregulation appears to be
captivating and promising.
Exposure to various inhaled antigens may induce the autoimmune
cascade leading to ASS. Exposure to potential environmental triggers
such as mould, birds, feather pillows, acting as initiating symptoms,
is exceptionally high mostly in individuals with pulmonary involve-
ment [27]. As compared to patients with other subtypes of IIM, those
with ASS were statistically more frequently exposed to inhaled anti-
gens such as dust, gases or fumes [28]. In the large international
cohort tobacco smoking was associated with an increased risk of
73
anti-Jo-1 formation in genetically susceptible IIM patients [29]. Fur-
thermore, positive association of respiratory tract infections and dis-
eases with a subsequent risk of developing IIM was suggested [30].
Murine models of autoimmune myopathies confirm that activation
of Toll-like receptors 7 and 8 is crucial in the initiation and mainte-
nance of the disease [31], which might suggest the role of intracellu-
lar respiratory pathogens like viruses. Subsequent cellular damage
leads to release of microparticles and activation of innate responses.
The pivotal role is attributed to NK cells which are differentiated
in active ASS. Hervier et al. described a significantly lower percentage
of fully functional NK cells in patients with ASS as compared to
healthy controls. NK cells in active ASS are characterized by increased
CD57 and Ig-like transcript 2 but decreased NKp30. The ability to pro-
duce IFN-y, both spontaneously and after stimulation, is significantly
impaired, while production of proteolytic enzymes and the degranu-
lation process remain intact. NK cells infiltrate the perimysium and
surround the myofibers. As compared to healthy controls, in the
lungs of ASS patients exceptionally high numbers of NK cells were
found. Furthermore, in patients with ASS, higher percentages of NK
cells expressing granzyme A and granzyme B were observed [32].
NETosis was also suggested to be important in the pathogenesis of
IIM and IIM-associated ILD (interstitial lung disease). In patients with
IIM, NET-inducing capacity is increased, while NETs degradation and
DNase I activity are impaired, especially in individuals with ILD, in
the course of IIM. Patients with anti-Jo1 antibodies were reported to
have an exceptionally low activity of DNAase I [33]. Seto et al. dis-
played that NET formation in IIM contribute to skeletal muscle dis-
ruption and decreased myotubes viability, probably via citrullinated
histones-mediated mechanisms. Increased neutrophil gene signature
in DM skeletal muscles correlated with markers of myocyte injury
and enhanced type I and II IFN responses. Levels of NETs were found
to be significantly higher in patients with anti-MDA5 and anti-TIF1
antibodies, yet not in anti-Jo-1 positive patients [34]. Further studies
are needed to evaluate the significance of neutrophil dysregulation in
ASS.
Anti-Jo-1 antibodies were found to be strongly associated with
HLA-B*08:01 and HLA-DRB1 03:01 polymorphisms. Associations
between particular amino acid positions and ARS subtypes were
identified as potentially even stronger than classical HLA associations
[35]. Risk variants observed in patients with IIM were found to be
similar to those revealed in other seropositive autoimmune diseases.
Performed so far genetic analysis supports the idea of shared aetiol-
ogy between ethnicities [36]. However, in the study by Johnson et al.
ASS patients with autoantibodies other than anti-Jo-1 were more
likely to be African-American than Caucasian or other race, suggest-
ing a possible association of ethnicity and ARS subtype [37]. Further
studies are needed to assess the importance of racial differences in
the pathogenesis of ASS.
Pathogenesis of ASS with the role of different autoimmune cells
have been presented on Fig. 1.
Diagnosis
In the recent years, new classifications and diagnostic criteria of
IIM and its subtypes have been proposed. Solomon’s criteria and Con-
nor’s criteria for ASS are in Table 1 along with EULAR/ACR criteria for
adult and juvenile IIM and its major subgroups [38 40]. Similarities
and differences between the classification criteria are also presented
in Fig. 2. Based on the analysis of 260 patients, four separate clusters
were distinguished such as inclusion body myositis, immune-medi-
ated necrotizing myopathy, dermatomyositis and antisynthetase syn-
drome [41]. Antisynthetase syndrome differs from other IIM due to
its unique features. Studies suggest that none of the criteria proposed
so far corresponds entirely with the clinically-based diagnoses. In
the latest EULAR/ACR criteria the distinctness of ASS was not
reflected. Since those criteria do not include autoantibodies
74 A.H. Opinc and J.S. Makowska / Seminars in Arthritis and Rheumatism 51 (2021) 72 83

Fig 1. Role of autoimmune cells in the pathogenesis of ASS. NK cell natural killer cell, APC antigen presenting cell.

other than anti-Jo-1, some of the ASS cases may be omitted [40].
According to Greco et al., EULAR/ACR criteria were met by 59.5% of
the patients with clinical suspicion of ASS or myositis, including all
anti-Jo1-positive patients but only 20% of patients with other ARS.
The authors proposed to modify the EULAR/ACR criteria by attribut-
ing the same weight as anti-Jo-1 now has to all ARS. If so, in 95% of
patients clinically-based diagnosis would be reflected by meeting the
formal criteria. Compliance with Solomon ‘s criteria was even weaker
in less than half of the 34 patients with suspected ASS or myositis
meeting the criteria [42].
As the spectrum of antisynthetase syndrome is heterogeneous
and not all of the typical symptoms have to be present, establishing a
proper diagnosis at the onset of the disease may be challenging.
Patients with antisynthetase antibodies are frequently diagnosed
with undifferentiated connective tissue diseases, idiopathic ILD,
interstitial pneumonia with autoimmune feature (IPAF), other

Table 1
Comparison of classification criteria for ASS and IIM.

Criteria Solomon’s Connor’s EULAR/ACR

Immunological Any ARS Any ARS anti-Jo-1

Clinical Major criteria: - ILD - Objective symmetrical weakness of upper
- ILD - PM/DM by Peter and Bohan and lower proximal extremities
- PM/DM by Peter and Bohan - Arthritis - Proximal leg muscles weaker than distal
Minor criteria: - Raynaud phenomenon - Neck flexors weaker than extensors
- Arthritis - Mechanic’s hand - Dysphagia/oesophageal motility disorders
- Raynaud’s phenomenon - Persistent, unexplained fever - Skin lesions (heliotrope rash, Gottron’s pap-
- Mechanic’s hand ules, Gottron’s sign)
- Age of onset
Additional examinations Not included Not included Typical features in muscle biopsy, elevated
concentrations of skeletal muscle enzymes
Criteria needed for stating diagnosis ARS + 2 major criteria or ARS + at least 1 of ARS + at least 1 of the clinical criteria Definite IIM: score of at least 7.5 (8.7 with
the major criteria with 2 minor criteria muscle biopsy)
Probable IIM: score of at least 5.5 (6.7 with
muscle biopsy)
 A.H. Opinc and J.S. Makowska / Seminars in Arthritis and Rheumatism 51 (2021) 72 83
Fig. 2. Diagnostic criteria for ASS and IIM: Solomon’s criteria (2011) in light grey frame, Connor’s criteria (2010)
frame.
connective tissue diseases or remain under observation with no final
diagnosis [43]. Due to numerous diagnostic challenges, final diagno-
sis is often delayed. An average diagnostic delay of six months was
described in patients with anti-Jo-1 antibodies [44]. In anti-PL-7 and
anti-PL-12-positive patients, a delay period is believed to be even
longer [45]. Evaluation by rheumatologist has been shown to be
highly indicated in patients with ILD. Compared to the standard
assessment performed by the team of pulmonologists, radiologists
and pathologists, independent evaluation by a rheumatologist
enabled to increase the number of connective tissue disease (CTD)-
ILD with autoimmune features by 77% (13 cases of CTD-ILD diagnosed
by standard team vs 24 CTD-ILD by rheumatologist). Noteworthy,
standard assessment missed 3 out of 4 cases of ASS, proving the criti-
cal role of the cooperation of medical professionals in diagnostic and
therapeutic procedures [46]. In addition, ASS criteria interfere partly
with the criteria of a novel diagnostic entity - interstitial pneumonia
with autoimmune feature (IPAF). IPAF was proposed in 2015 by the
European Respiratory Society (ERS) and American Thoracic Society
(ATS) “Task Force on undifferentiated Forms of connective tissue dis-
ease-associated interstitial lung disease” to describe patients with
ILD and features of autoimmune disorders, yet not fulfilling the crite-
ria of any connective tissue disease. Diagnosis of IPAF may be stated
if a patient present at least one feature in each of at least two domains
clinical domain (including symptoms such as RP, mechanic’s hands,
Gottron’s sign, arthritis, palmar telangiectasia, digital oedema, distal
digital tip ulcers), serologic domain (ANA in the titre of at least 1/320,
nuclear or centromere pattern of ANA regardless of the ANA titre,
presence of several specific antinuclear autoantibodies including
antisynthetase antibodies, anti-CCP or RF exceeding twice or more
the upper limit) and morphologic domain (ILD in high resolution
computed tomography or lung biopsy, multi-compartment involve-
ment) [47]. Fulfilling the criteria of any connective tissue disorder
75
in black frame, EULAR/ACR criteria for IIM (2017) in dark grey
excludes IPAF. However, an oligosymptomatic patient not classified
as ASS according to EULAR/ACR or Solomon criteria may be diagnosed
with IPAF or either with ASS according to the broadest Connor’s
criteria.
Clinical symptoms
ASS is characterised by a combination of symptoms such as myo-
sitis, arthritis, interstitial lung disease, Raynaud phenomenon,
mechanic’s hands and fever. Although some of the symptoms are
more commonly seen in patients with define ARS type, patients with
ASS develop in general alike clinical presentation. The prevalence of
each symptom varies depending on the study. According to Euro-
Myositis Registry, patients with ASS most often suffer from muscular
lesions and interstitial lung disease (90% and 71%, respectively), while
the other symptoms are less prevalent [8]. It is noteworthy that clini-
cal presentation may alter with time as symptoms continue to
emerge gradually. At the onset of the disease, patients with anti-Jo-1
antibodies commonly present isolated arthritis, whereas in those
with anti-OJ, the sole symptom observed most frequently was myosi-
tis, while isolated ILD was the most common manifestation in anti-
PL-7, anti-PL-12 and anti-EJ-positive individuals. With time, other
symptoms appeared and in the majority of the patients the complete
triad, i.e. myositis, arthritis, ILD, was found, yet isolated ILD remained
the most common presentation in anti-PL-12 and isolated myositis in
anti-OJ-positive patients [45]. Prevalence of symptoms typical for
ASS in various cohorts is presented in Table 2. It should be noted that
cohorts vary significantly as for the numbers of patients and selection
criteria, what could lead to biased conclusions. It cannot be excluded
that the incidence of symptoms, especially in the subgroups of
patients with less prevalent autoantibodies, may be falsely high due
to limited number of cases described.
76 A.H. Opinc and J.S. Makowska / Seminars in Arthritis and Rheumatism 51 (2021) 72 83

Table 2
Review of cohorts of patients with ASS or ARS.

Author Year N Myositis (%) Arthritis/Arthralgia ILD (%) Skin lesion (%) RP (%) Fever (%)
(%)

Cavagna et al. (AENEAS collabo- 2019 828 with ARS 78.7 66.4 81.4 36.6 (MH) 38.2 35
rative group institution) [45] 593 anti-Jo-1 82.1 74.2 82 37 (MH) 37 36
95 anti-PL-7 80 49.5 76.8 42(MH) 50 34
84 anti-PL-12 51.2 41.7 69 45 (MH) 56 53
38 anti-EJ 84.2 52.6 89.5 39 (MH) 39 37
18 anti-OJ 77.8 44.4 61.1 39 (MH) 22 6
Lilleker et al. (EuroMyositis 2017 512 ASS 90 (muscle 50 71 38 (MH) 3 (calcino- 51 No data
Registry) [8] weakness) sis, ulceration)
44 (rash) 32
(erythema)
Hervier et al. [48] 2012 233 ASS 57 63 (arthralgia) 20 77 19 (MH) 42 28
(arthritis)
Cavagna et al. [44] 2015 225 anti-Jo-1 55.56 64.5 50.67 19.35 (MH) 23.53 N = 221 25.68 N = 222
N = 217
Trallero-Aragu
as et al. [15] 2016 148 anti-Jo-1 83.1 70.1 81.8 44.9 (MH) 34.5 33.3
Shi et al. [5] 2017 124 with ARS 63.7 (muscle weak- 54 94.4 46 (MH) 44.4 (Got- 9.7 No data
ness) tron’s papules/
36.3 (myalgia) sign)
21.8 (heliotrope
rash)
Noguchi et al. [7] 2017 51 with ARS 100 (muscle weak- 41 80 31 (MH) 8 39
ness) 67 (rash)
45 (myalgia) 27 (Gottron’s sing/
papule)
14 (Heliotrope rash)
Vulsteke et al. [49] 2019 51 anti-OJ 75 (myositis) 31 90 36 (MH) 29 (DM 12 38
skin lesions)
Opinc et al.* 2020 50 with ARS 48.00 58 32 4 (MH) 34 (other) 12 8
35 anti-Jo-1 40 54.3 28.6 2.9 (MH) 34.3 14.3 5.71
(other)
4 anti-PL-7 75 75 25 25 (MH) 100 (other) 0 0
9 anti-PL-12 77.8 66.7 33.3 11.1 (MH) 44.4 11.1 22.2
(other)
3 anti-OJ 66.7 33.3 33.3 0 (MH) 0 0
0 (other)
2 anti-EJ 0 100 100 0 (MH) 50 (other) 0 0
Masiak et al. [43] 2020 50 with ARS 56 72 (arthralgia) 36.1 52 48 (skin lesions) 14 26
(arthritis)

et al. [50]
Szabo 2018 49 anti-Jo-1 100 88 73 33 (MH) 6 65 43
(calcinosis)
Zhang et al. [4] 2020 46 anti-EJ 41.3 (muscle weak- 23.9 96.7 56.5 (MH) 23.9 8.7 60.9
ness) (heliotrope rash)
30.4 (myalgia) 41.3 (Gottron’s pap-
ules)
19.6 (V sign)
21.7 (shawl sign)
Marie et al. [51] 2012 36 anti-Jo-1+ and 75 (muscle weak- 69.4 77.8 55.6 (MH) 50 No data
anti-Ro52+ ness)
88.9 (myalgia)
Debray et al. [52] 2014 33 ASS 45 (myositis) 61 100 26 (MH) 21 (cutane- 24 30
51 (myalgia) ous signs of DM)
Marie et al. [53] 2013 15 anti-PL 93 26.7 93.3 33.3 (MH) 40 No data
ASS antisyntetase syndrome, ARS antisynthetase antibodies, N number of patients, ILD interstitial lung disease, RP Raynaud Phenomenon, MH Mechanic’s hands.
* results ahead of print.

Myositis Typically, ASS patients experience weakness in the proximal

The spectrum of muscular involvement in ASS ranges from
isolated increased serum concentrations of muscle enzymes to
severe weakness and mobility impairment [54]. Muscle weakness
was observed in 41.3 100% of ASS patients, while 30.4 88.9% of
them were affected by myalgia (Table 2). Noteworthy, in the
most numerous cohorts high incidence of muscle symptoms was
described (Table 2). Both myalgia and muscle weakness occur
more frequently in anti-Jo-1-positive patients than in those with
anti-PL-7 and anti-PL-12 [48,51]. As compared to patients with
other ARS, anti-OJ-positive patients could be at risk of developing
more debilitating myositis with severe muscle weakness and
atrophy [49].
muscles of upper and lower extremities, approximately one in three
patients is affected by neck muscle weakness and muscle atrophy [7].
Hypomyopathic or amyopathic onset is less typical in patients with
ARS [45,49]. It was observed in 33.3% of patients with anti-OJ but in
15.2% of anti-Jo-1 patients only, however, the differences did not
reach statistical significance [45,49]. Involvement of the oesophageal
muscles with subsequent dysphagia was observed in one third of
patients [7]. Isolated myalgia without muscle weakness was also
described [54]. Peripheral limb muscles involvement with fasciitis
remain rather casuistic [55]. According to Andersson et al., MRI
examinations of the thigh muscle revealed abnormalities in 65% of
patients with ASS. Muscle oedema was observed predominantly in
the anterior compartment while lesions indicating muscle damage
 A.H. Opinc and J.S. Makowska / Seminars in Arthritis and Rheumatism 51 (2021) 72 83
and fatty replacement mostly in the posterior compartment. Reduc-
tion of muscle volume was confirmed in 14% of ASS patients. In most
cases, muscular lesions were symmetrical [56]. Perifascicular necrosis
and macrophagocytosis are the most characteristic findings in muscle
biopsies. Perimysium, predominantly areas around the vessels, are
infiltrated by macrophages and CD8 lymphocytes. Alkaline phospha-
tase activity is highly expressed in the perimysium [57]. Contrary to
polymyositis and inclusion body myositis, no infiltrates in the endo-
mysium are observed. Increased expression of major histocompati-
bility complexes class I and II (MHC I and MHC II) were observed in
the cytoplasm and on the sarcolemma of myofibers, predominantly
in the perifascicular region [7]. Fibers in the perimysial area were
found to accumulate C5b-9 complexes on the sarcolemma or within
the sarcoplasm [57]. Diffuse necrotic and regenerating myofibers are
less frequently observed, yet may be associated with anti-OJ antibod-
ies as biopsy-based studies revealed a higher prevalence of diffuse
myofiber necrosis in anti-OJ-positive patients as compared to the
anti-OJ-negative group [7]. The presence of myonuclear actin fila-
ment inclusions distinguish ASS from other IIM subtypes with 93.3%
specificity and 80.1% sensitivity. Myonuclear actin aggregation may
be the consequence of impaired actin filament formation and shut-
tling, as reported by Stenzel et al. [57].
Interstitial lung disease
Interstitial lung disease (ILD) was observed in 50.67 100% of ASS
patients from various cohorts (Table 2). Considering ASS patients
with all ARS subtypes, included in the two most numerous multi-
centre registries prevalence of ILD reached 71 81.4% (Table 2).
According to the data from AENEAS base, ILD is the most common ini-
tial manifestation in patients with anti-PL-7, anti-PL-12 and anti-EJ
antibodies [45]. In the course of ASS, ILD is more prevalent in
anti-PL-7 and anti-PL-12-positive patients as compared to other ARS
subtypes [58]. Furthermore, in patients with anti-PL-7 and anti-PL-12
antibodies ILD is more frequently symptomatic and persistent [58].
The most common clinical manifestation of ILD is dyspnoea on exer-
tion [15]. Nevertheless, approximately one in five patients experience
an asymptomatic course of ILD which seems to be more prevalent in
anti-Jo-1 cases than in individuals with remaining ARS [45]. More-
over, in patients with anti-PL-7 and anti-PL-12, ILD is usually more
severe with lower FVC and DLCO and more prominent fibrosis as
compared to anti-Jo-1-positive patients [6]. On the contrary, FVC and
DLCO were reported to be higher in anti-CCP-positive ASS patients
[59]. Black race was found to be an independent risk factor of severe
ILD in the course of ASS. Comparing to white race, black patients had
statistically lower FVC and DLCO [6]. Muscular involvement can also
contribute to weaker respiratory capability. Ventilatory impairment
due to skeletal muscle weakness is more frequently observed in anti-
Jo-1 positive patients [51]. It is noteworthy that ILD can occur in
patients with no signs of myopathy [60], which contributes to
delayed diagnosis. Cases of acute respiratory distress syndrome are
not infrequent, even as an initial presentation of ASS [15,61,62].
Acute onset of ILD was observed in as many as 74.1% of patients with
anti-EJ and not more than half of patients with other ARS, yet the dif-
ferences between the groups did not reach statistical significance
[45]. Rapid progression of ILD was statistically more frequent in the
anti-PL-7-positive group than in anti-PL-7-negative patients. In indi-
viduals with a rapidly progressive ILD, higher proportions of neutro-
phils in BALF were observed, whereas in patients with anti-Jo-1
higher proportions of lymphocytes were reported [5]. Human neutro-
phils peptides in BALF correlated with the percentage of reticular
opacities and were suggested to correspond with disease activity in
ASS [63].
CT scans and lung biopsies usually display non-specific interstitial
pneumonia (NSIP) in 39 72.5% of the analysed patients with ASS or
organising pneumonia (OP) pattern in 14.6 43%, followed by a less
77
common usual interstitial pneumonia (UIP) observed in up to 9.76%
of patients [4,5,16,52,64]. Cases of organizing diffuse alveolar damage
(DAD) were reported in anti-EJ-positive patients [65]. Bilateral
ground-glass opacities and reticulations are predominant findings in
CT scans of ASS patients. Examinations frequently reveal also lower
volume loss, thickening of interlobular septum and bronchovascular
bundles, traction bronchiectasis as well as air-space consolidation.
Typically, lesions are located in the peripheral or basal areas. Honey-
combing is rarely observed [52,64]. At the initial presentation,
patients with anti-PL-12 antibodies showed more intense reticula-
tions and traction bronchiectasis as compared to anti-Jo-1 patients,
however, in a follow-up no differences were observed [52]. UIP pat-
tern, DLCO<45% at the time of diagnosis, respiratory muscle involve-
ment, ILD without myosis and older age were associated with poorer
prognosis of ASS-associated ILD [53,66]. Also pulmonary hyperten-
sion significantly worsens the prognosis, as only 58% of patients with
ASS-associated pulmonary hypertension survived three years
[48,67].
Arthritis and arthralgia
Arthritis and arthralgia are common signs in ASS with the preva-
lence varying significantly from 20 to 88% in different cohorts of
patients [50,68]. In the cohorts with the biggest study groups preva-
lence of articular involvement was estimated as 50 66.4% (Table 2).
According to the data from the AENEAS collaborative group, arthritis
occurs more frequently in anti-Jo-1 patients as compared to those
with other ASS subtypes. In 24% of patients with anti-Jo-1 antibodies,
isolated arthritis was the initial symptom of the disease [45,69,70].
Joint inflammation in the course of ASS usually manifests itself as
symmetrical polyarthritis affecting predominantly proximal inter-
pharyngeal, metacarpophalangeal or wrist joints [44,59]. Larger
joints, such as the knees, elbows, shoulders, ankles or hips, as well as
distal interpharyngeal or feet joints are less frequently involved
[59,71]. In a minority of patients, oligoarticular or asymmetrical
arthritis is observed. The oligoarticular type was observed more fre-
quently in anti-OJ-positive patients, yet the difference did not reach
statistical significance [45]. Synovitis, periarticular calcifications or
isolated arthralgia were also reported [54,71,72]. Prevalence of anti-
CCP antibodies in ASS patients with arthritis ranges from 4.96% to
13.5%, while RF can be found even in 31.5% of patients [44,73,74].
Patients with anti-CCP antibodies are at risk of developing severe
arthritis as compared to anti-CCP-negative group [7]. The number of
swollen joints was significantly higher if a patient was anti-CCP-posi-
tive. In 87% of ASS patients with anti-CCP antibodies, features of
radiographic damage were found, while in anti-CCP-negative
patients it was far less prevalent [59]. The course of arthritis may dif-
fer depending on the time of appearance. Researchers suggest that if
arthritis is an initial manifestation, it usually develops as rheumatoid
arthritis-resembling type with symmetrical and polyarticular
involvement, presence of rheumatoid factor and features of erosion
in radiography, while a late-onset arthritis rather resembles arthritis
in connective tissue diseases [75]. In some patients, improper diagno-
ses of rheumatoid arthritis or other connective tissue diseases are
established, especially in cases of isolated arthritis [59]. According to
Lefevre et al., 60% of patients with arthralgia were treated with at
least one DMARD for seronegative polyarthritis until the final diagno-
sis of ASS was made [71]. In patients with isolated arthritis, median
diagnostic delay is exceptionally high reaching even two years [15].
Raynaud phenomenon, fever and cutaneous symptoms
Data on the frequency of Raynaud phenomenon (RP) in ASS is
highly inconsistent. Depending on the study group, the prevalence
ranged from 8.7% to 65% of patients [4,15,43,44,49,50]. Considering
the two biggest international registries RP was observed in 38.2 51%
78 A.H. Opinc and J.S. Makowska / Seminars in Arthritis and Rheumatism 51 (2021) 72 83
(Table 2). In a study by Cavagna et al., RP was an initial symptom in
17% of patients with anti-Jo-1 antibodies [44]. RP was reported to be
more frequent in patients with polyarthritis in the course of ASS as
compared to patients with myositis and/or ILD [15]. In the cohort of
ARS-positive patients, a subgroup with anti-PL-12 antibodies was
most frequently affected by RP [45]. In a single study, RP was associ-
ated with anti-PL-7 antibodies [76], yet in another research no statis-
tical differences concerning RP were found between anti-Jo-1-
positive patients and anti-PL-7 and PL-12-positive group. Neither
were any differences observed for the mechanic hands or fever [51].
Nailfold capillaroscopy is a non-invasive tool, enabling to display
microvascular lesions and differentiate between primary and second-
ary RP. In the study by Sebastiani et al. abnormalities in nailfold capil-
laroscopy in the form of giant capillaries, avascular areas,
microhemorrhages or ramifications were observed in 62.1% of ASS
patients. Avascular areas, observed in 17.9%, were associated with RP,
myositis, anti-SSA and anti-Jo-1 antibodies. Scleroderma-resembling
pattern was described in over 35% of cases, predominantly with lon-
ger disease duration or anti-Jo-1 antibodies, yet did not corelate with
the presence of RP. Noteworthy, such pattern was observed in
approximately 1/3 cases of ASS patients without RP, suggesting that
nailfold capillaroscopy may provide a valuable diagnostic hint in
patients without unequivocal clinical presentation [77].
The prevalence of fever occurs in 25.5% - 60.9% of patients
[4,15,44,50,51]. In the study by Cavagna et al. the incidence of fever
in ASS cohort reached 35% and it was most common in anti-PL-12-
positive group [45]. A case of a patient with fever of unknown origin,
enhanced FDG uptake in the proximal shoulder muscles and pulmo-
nary abnormalities in PET/CT was diagnosed as anti-Jo-1-postive ASS
[78].
Mechanic’s hands (MH), defined as fissured, scaly, non-itching
hyperkeratotosis, located at the palmar and lateral sides of the hands
and fingers, are one of the hallmarks of ASS. However, distinguishing
those lesions from other cutaneous conditions may be challenging
[79]. Depending on the study, prevalence ranged from 19% to 56.5%
of patients with ARS [4,5,7,8,15,43,44,48,50]. Considering the inci-
dence in the biggest international cohorts 36.6 38% of ASS patients
manifested with MH (Table 2). MH were reported to occur more fre-
quently in patients with anti-Jo-1 antibodies as compared to other
subtypes of ARS [68]. In another study on an ARS positive cohort,
anti-PL-12-positive patients most frequently manifested MH [70]. No
cases of isolated MH as an initial symptom of ASS were described
[8,54]. Recently, similar lesions on the plantar side and toes were
described as “hiker’s feet” in nine patients with ASS and dermatomy-
ositis. In 89% of them both MH and hiker’s feet were observed simul-
taneously [80]. Further studies are needed to evaluate the prevalence
of this newly described sign. Skin lesions such as Gottron’s papules/
sign, heliotrope rash, shawl, holster or V sign, typically seen in der-
matomyostis, were also observed in patients with ASS [49]. Helio-
trope rash was more often reported in patients with anti-PL-7 than in
an anti-Jo-1 and anti-EJ-positive group [5]. Erythema around the nail
folds, subcutaneous calcinosis, ulcerations or sclerodactyly were also
reported in patients with ASS or overlapping scleroderma with ASS
[8,49,81].
Symptoms not included in classification criteria
Apart from the symptoms included in the classification criteria, a
broad spectrum of other manifestations may be observed in patients
with ASS . Gastrointestinal symptoms are frequently reported and
tend to be more common in patients with anti-PL-7 and anti-PL12
antibodies [53,58]. According to Casal-Dominguez et al., even 25% of
ASS patients suffered from dysphagia and 19% had regurgitations due
to decreased lower oesophageal sphincter pressure [82]. A case of
oropharyngeal dysphagia with subsequent cachexia triggered by
decreased pressure of the upper oesophageal sphincter was reported
in an anti-Jo-1-positive patient [83]. Sicca syndrome can affect 33% of
ASS patients, however, these symptoms are not included in the classi-
fication criteria [52]. A case of oral ulceration was noted [84]. Rare
incidence of bilateral vocal fold bamboo nodes accompanied with
glottic impairment and hoarseness was reported in an anti-Jo-1-pos-
itve patient with elevated muscle enzymes, arthralgia and ILD [85].
Ophthalmic complications such as retinal vasculitis, intraretinal hae-
morrhages, subretinal fluid, macular thickening and clinical manifes-
tation of a sudden blurry vision were reported in a patient with ASS
history [86]. Non-specific symptoms such as general malaise and
weight loss are not infrequent [54,87]. Progressive renal failure,
hypertension and thrombotic microangiopathy resembling sclero-
derma renal crisis appeared in a anti-PL-7-positve patient with ASS
[88].
Cardiovascular involvement in the course of IIM has been the sub-
ject of interest in recent years as it can significantly contribute to
both clinical presentation and prognosis [89]. Cardiovascular mani-
festations can also emerge in the course of ASS. Myocarditis can be an
initial manifestation or can occur with the disease progression, lead-
ing to congestive heart failure [90]. Atrial arrhythmia, bundle branch
blocks, sinusal tachycardia or repolarization abnormalities were
reported [91]. Prevalence of pericarditis varies from 10.5% to even
50% of patients, yet the study groups were limited [5,91]. Pericardial
effusion was reported in 20% of patients [53]. Based on echocardiog-
raphy and right heart catheterisation, pulmonary hypertension was
confirmed in 7.9% of ASS patients [92]. Elevated troponins T and I,
observed in ASS, can falsely suggest acute coronary syndromes [91].
Valvular lesions, although seldom reported, may lead to severe condi-
tions requiring valvular replacement [93]. In patients with ASS,
higher prevalence of metabolic syndrome and insulin resistance was
noted [94].
Outcome and prognosis
Mortality in ASS is considered to be significantly higher than in
the general population [15,95], however, in a single observation it
was not confirmed [6]. The cumulative ten-year survival rate in
patients with various ARS was estimated as 76.8% [5], yet data varies
depending on the study. Main causes of death in anti-Jo-1-positive
patients included interstitial lung disease, neoplasm, infectious dis-
eases including pneumonia, severe myositis and cardiovascular dis-
orders [15,67,96].
Risk of neoplasm
Incidence of cancer in ASS patients is not fully recognised. Accord-
ing to Hervier et al. the frequency of cancer in ASS patients did not
differ from the incidence observed in general population [48]. How-
ever, majority of available literature reports on neoplasm in ASS have
been conducted when the awareness of ASS was limited and there-
fore significant number of cases could have been underdiagnosed or
falsely diagnosed as other subtypes of IIM. In approximately 12% of
ASS patients from the Spanish cohort, cancers were diagnosed with a
median delay of 72 months [15]. In the cohort of 28 patients with
ASS 14% prevalence of cancer was described including diagnoses of
respectively lung adenocarcinoma, primary liver cancer, colon adeno-
carcinoma and melanoma stated after the diagnosis of ASS was posed
[97]. Similarly, in a long-term observation performed by Mileti et al.
neoplasms (thymoma and breast cancer) occurred in 13%, yet study
group was limited to 15 cases [98]. Several cases and case series of
neoplasm in course of ASS were reported [99 101]. According to lit-
erature analysis performed by Boleto et al. the most commonly
observed neoplasms in ASS patients include lung, colorectal, breast,
ovary and liver cancers [99]. Neoplasm was less frequently observed
if ASS manifested with fever, Raynaud’s phenomenon, ILD and arthri-
tis [102], suggesting that in patients with IIM typical presentation of
 A.H. Opinc and J.S. Makowska / Seminars in Arthritis and Rheumatism 51 (2021) 72 83
ASS could be a protective factor, reducing the possibility of cancer.
Nevertheless, active screening and oncological awareness seem to be
highly advisable.
Clinical prognostic factors
An older age at the time of diagnosis, severe pulmonary involve-
ment, ILD without myositis, cancer, oesophageal involvement and
calcinosis were identified as risk factors of a severe course of ASS
[5,15]. Assessing CT pattern is crucial, since UIP is associated with
poorer prognosis [92]. On the contrary, arthritis and muscle weak-
ness at the time of diagnosis were reported as favourable prognostic
factors [67,95].
Serological prognostic factors
Increased ferritin serum concentration was identified as a risk fac-
tor of a severe ASS course [5]. According to most of the studies, sur-
vival in ASS is not related with the type of ASS [16,45,58], however
Hervier et al. reported anti-PL-7 and anti-PL-12 profiles as associated
with poorer prognosis [48]. A majority of fatal outcomes occurred
within the first year of the disease and, in most cases, it concerned
patients with anti-PL-7 [5,16]. In patients with anti-PL-7 or anti-PL-
12, ILD more frequently led to fatal outcome as compared to anti-Jo-
1-positive patients with ILD. However, in patients with anti-Jo-1 anti-
bodies remission of myositis occurred less frequently and they more
often developed relapse than patients with anti-PL-7 and anti-PL-12
antibodies [58]. Co-occurrence of anti-Jo-1 and anti-Ro52 antibodies
was related with a higher risk of myositis and arthritis exacerbation,
a symptomatic severe form of ILD and increased risk of neoplasm
[51].
Impact on the quality of life
ASS significantly impacts the quality of life. Although in 65% of
patients muscle weakness improved after therapy, only 18% of them
experienced remission. In 17%, relapse of myositis was observed.
Daily functioning was impaired in approximately a quarter of ASS
patients, mostly due to adverse effects of steroids therapy and skin
calcinosis [96]. However, median HAQ-DI (Health Assessment Ques-
tionnaire- Disability Index) score in patients with ASS was lower
than in sIBM, PM and overlapping syndromes [8].
Overview of treatment possibilities
As IIM are rare disorders, no large randomized controlled trials are
available. Therefore, therapy recommendations are based on trials
with limited number of cases, retrospective analyses and expert opin-
ion. Despite the significant clinical differences between the IIM sub-
types, majority of the studies were conducted on the IIM group as a
whole. Randomized control studies on larger groups are required to
assess the effectiveness of different therapeutic options.
Corticosteroids
Corticosteroids are considered to be the first line therapy in
patients without contraindications. Typically, steroids in the initial
dose of 0.5 1 mg/kg/day of oral prednisolone are administered. In
severe or multiorgan myositis, treatment can be started with 3 to
5 days of intravenous high dose pulses of 250 1000 mg methylpred-
nisolone per day. Treatment in the initial dose is maintained usually
for 4 12 weeks until clinical improvement and decrease in CK con-
centrations are observed. The dose is then subsequently tapered by
20 25% monthly to the minimal required maintenance dose which is
usually approximately 5 10 mg of prednisone per day [103 105].
High single-dose alternate-day prednisolone therapy was proposed
79
as an effective and safer than every-day treatment algorithm in poly-
myositis patients [106]. In the randomised controlled trial oral pulses
of dexamethasone in the dose of 40 mg per day administered for
4 days a month showed similar efficacy as standard daily doses, yet
ensured reduction of side-effects [107].
Other immunosuppressive agents
In milder cases, corticosteroid monotherapy provides adequate
disease control, yet most patients require additional immunosup-
pressive agents [105]. In many cases steroid-sparing agents are added
to ensure better disease control and tapering of the steroids [7].
According to the literature, over half of the patients are treated with
the combination of steroids and other immunosuppressive drugs
[7,50]. Methotrexate (MTX), cyclophosphamide and azathioprine
(AZA) were frequently administered. Mycophanolate mofetil (MMF),
antimalarial drugs and sulphasalazine are also prescribed. Usage of
calcineurin inhibitors such as cyclosporin and tacrolimus was
reported, yet due to severe side effects, calcineurin inhibitors are gen-
erally reserved for refractory patients [7,8,50,108]. In patients with
refractory myositis biological agents or intravenous immunoglobu-
lins (IVIG) can also be added.
According to Marie et al., effectiveness of steroid-sparing agents in
anti-Jo-1-positive group was estimated as 83.3% for methotrexate
and 72% for azathioprine, respectively [96]. MMF led to improvement
in 57.1% of patients with myositis refractory to MTX and AZA [96].
Other retrospective evaluation of IIM patients showed higher long-
term survival rates in patients treated with MTX as compared to AZA
[109]. Despite promising retrospective data, adding MTX or cyclo-
sporin (alone or in combination) to corticosteroid therapy did not
lead to clinical improvement in double-blind placebo-controlled ran-
domized controlled trial [110]. IVIG in the dose of 1 g/kg for two days
a month are administered in refractory cases and were reported to
improve clinical condition in 69,2% of patients [96]. Beneficial effects
of IVIG have been observed as for the muscle strength [111]. IVIG
therapy should be considered especially in patients with oesophageal
complaints, as immunoglobulins infusions led to alleviation of oeso-
phageal symptoms in 90% of patients with ASS-related oesophageal
involvement [96].
Patients with ASS-related ILD are at risk of poor response to
corticosteroid monotherapy. According to Cavagna et al., neither
of 17 patients with anti-Jo-1 antibodies and ILD responded to
prednisone monotherapy [112]. Retrospective analysis showed
similar efficiency of AZA, MMF and cyclophosphamide as for the
improvement of pulmonary involvement and steroid-dose taper-
ing in PM/DM patients [113]. Both AZA and MMF proved to be
effective in IIM-associated ILD. In patients treated with AZA,
lower doses of steroids were needed yet adverse effects were
more common [114]. amongst patients with ASS-associated ILD,
89.4% benefited from infusions of cyclophosphamide [96]. Effec-
tiveness of cyclosporin was confirmed in the cohort of steroid-
resistant anti-Jo-1-positive patients with ILD [112]. A significant
improvement in pulmonary parameters and muscle strength was
also described in anti-ARS-positive patients treated with tacroli-
mus [115]. Cases of ASS patients successfully treated for myositis
or ILD with plasmapheresis were reported [116,117].
Biological agents
Rituximab emerges as a promising therapeutic option for
multi-drug refractory myositis with ILD [118 120]. According to
the study by Andersson et al., the median percentages of pre-
dicted FVC, FEV1 and DLCO increased by 24%, 22% and 17%,
respectively, while the extent of ILD in HRCT scans decreased by
34% after RTX therapy [120]. In another study, RTX lead to stabili-
zation or improvement in CT score and FVC of 88% and 79% of
80 A.H. Opinc and J.S. Makowska / Seminars in Arthritis and Rheumatism 51 (2021) 72 83
patients, respectively. Increase in total lung capacity was noted,
as well as an improvement in DLCO after three years [121]. Addi-
tion of RTX enabled to tapper the dose of prednisone by almost
half [121]. Andersson et al. noted high prevalence of fatal infec-
tions in the group of ASS patients treated with RTX. Although
infections were the main cause of death in this study, the overall
mortality rate was comparable in the RTX-treated group and
non-RTX-treated patients. Noteworthy, 10 out of 12 patients with
acute onset or exacerbation were on combined therapy with RTX
and cyclophosphamide [120], combining two immunosuppressive
agents could have aggravate the risk of fatal infections and there-
fore high infection rate cannot be attributed solely to the use of
RTX. The Rituximab in Myositis (RIM) trial compared the effi-
ciency of RTX in patients with IIM refractory to steroids and at
least one other immunosuppressive drug, depending on the time
of RTX administration. In 83% of the patients their condition
improved yet no differences were observed between early-RTX
and late-RTX administration. It should be emphasized that
patients with ARS and anti-Mi-2 autoantibodies were more prone
to benefit from RTX therapy [122].
Effectiveness of other biological agents is less recognized. A
significant reduction of symptoms was observed in a patient with
myositis, arthritis, ILD and remitting fevers treated with subcuta-
neous anakinra (anti-IL-1 receptor antagonist) in the daily dose of
100 mg [123]. Anti-Jo-1 positive patient with rash, arthritis, myal-
gia with increased CK, RP and fever was reported to be success-
fully treated with the combination of tocilizumab (anti-IL-6
agent, in the dose of 8 mg/kg a month), MTX and steroids [124].
Tocilizumab was also effective in alleviating muscular involve-
ment in two patients with refractory polymyositis [125]. Data on
anti-TNF agents remain rather unfavourable [104]. In a case series
of five DM patients, etanercept (TNF inhibitor) therapy was dis-
continued due to exacerbation [126]. Infliximab (TNF inhibitor)
treatment was not effective in IIM either [127]. In a randomized,
double-blind trial on DM patients, etanercept was found to tapper
the steroid dose better than placebo, yet no significant differences
were observed as for the functional outcome [128]. According to
the results of phase IIb randomised treatment delayed-start trial,
abatacept (CTLA-4-Ig) seems to be a promising therapeutic option
for patients with refractory PM/DM [129]. Ustekinumab (anti-IL-
12 and anti-IL-23 agent) proved to be effective in treating refrac-
tory mechanic’s hands, one of the symptoms seen in ASS [130].
Fig. 3. Proposed algorithm for patients with the ASS spectrum symptoms. ARS
Recently, studies are ongoing to assess the effectiveness of JAK
inhibitors as therapeutic agents in IIM [131 136].
Other therapeutic interventions
Percutaneous endoscopic gastrostomy or gastric intubation may
be necessary in case of oesophageal involvement [96]. Approximately
14% of patients with anti-Jo-1 or anti-PL-7 antibodies require oxygen
therapy due to severe ILD [48,66]. In rare cases, pharmacotherapy
remains ineffective and lung transplant is required [137]. Individually
adapted physical exercise should be recommended for myositis
patients as it reduces activity limitations and imposes anti-inflamma-
tory effect [138].
Limitations and unmet needs
Strong limitation of this review is that many of the included
cohorts of patients with ASS are limited, what could lead to biased
conclusions, especially in the subgroups of patients with less preva-
lent subtypes of ARS. In such limited groups risk of bias is significant,
as observations might be coincidental or severe cases (as more obvi-
ous to diagnose) could be favoured, suggesting a more debilitating
course of the disease. Presumably data from multicentre registries
present in general more reliable clinical presentation of ASS, yet
descriptions of rarer outcomes from smaller cohorts should not be
disregarded. With the incidence as low as in ASS, it could be expected
that less frequent clinical presentations may be difficult to capture.
Therefore, by incorporating all available cohorts the possibility of
missing some rarer presentations was reduced. However, multicentre
studies and long-term observations of ASS cohorts are needed to
form more accurate conclusions. Furthermore, lack of unified diag-
nostic criteria results in versatile inclusion criteria in different
cohorts, making it difficult to state reliable comparisons. Defining the
overriding criteria of ASS is critical for proper diagnosis and future
research. Heterogenicity of the patients included into various cohorts
as for the ethnicity could also lead to possible bias. Black race was
found to be strongly associated with severe ILD in the course of ASS,
yet little is known so far about the impact of ethnicity on the course
of other clinical presentations and laboratory results. Presumably,
many cases of ASS remain underdiagnosed. Active interdisciplinary
cooperation of many medical professionals (e.g. rheumatologists, pul-
monologists, dermatologists, radiologists) is highly indicated to
antisyntetase antibodies, ASS antisynthetase syndrome, ILD interstitial lung disease.
 A.H. Opinc and J.S. Makowska / Seminars in Arthritis and Rheumatism 51 (2021) 72 83
reduce the number of underdiagnosed cases. Moreover, ASS is still a
poorly-recognized entity, even amongst professionals dealing with
musculoskeletal or lung diseases. Raising awareness about this rare
syndrome is essential. The real incidence of neoplasm in ASS is diffi-
cult to estimate, as majority of data is derived from case reports or
case series and in older studies cases of ASS could be falsely identified
as other subtypes of IIM due to low awareness of the disease. Other
limitation is that majority of the therapeutic recommendations are
extrapolated from the studies on patients with IIM in general and it is
not certain that they will be equally effective in ASS cohorts. Further
studies, dedicated solely for patients with ASS, are required to form
credible recommendations.
Conclusions
ASS is a complex disease with a lot of possible clinical presenta-
tions. Although classified as IIM, myositis may not necessarily be the
prominent manifestation. The currently available classification crite-
ria do not fully correspond with the clinical patterns of the disease.
Since symptoms of ASS can emerge gradually, sometimes after a long
time, the disease should be considered as a heterogeneous spectrum
rather than a homogenous disease entity. To prevent underdiagnoses,
each patient with confirmed presence of ARS and at least one symp-
tom representing the ASS spectrum should remain under long-term
interdisciplinary observation (Fig. 3). Randomized controlled trials,
dedicated for patients with ASS are needed to form treatment algo-
rithms.
Declaration of Competing Interest
None.
Funding
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
Authors contribution
Aleksandra Halina Opinc: Conceptualization, Investigation, Formal
Analysis, Writing - Original Draft, Joanna Samanta Makowska: Con-
ceptualization,Writing - Review & Editing, Supervision
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