Keywords
antisynthetase syndrome - antisynthetase antibodies - interstitial lung disease -
idiopathic inflammatory myopathies - connective tissue disease - idiopathic interstitial
pneumonia
Idiopathic inflammatory myopathies (IIMs) constitute a group of autoimmune disorders
that encompasses several myopathy forms.[1] Antisynthetase syndrome (ASyS) is a myopathy that is distinguished by the presence
of antibodies targeting several aminoacyl-transfer RNA synthetases (ARSs). First described
by Hochberg et al who associated anti-Jo antibodies with interstitial lung disease
(ILD) in myositis patients,[2] Marguerie et al later emphasized the clinical spectrum and the triad of polymyositis,
arthritis, and ILD in the presence of autoantibodies to ARSs.[3] Today, the syndrome has evolved with more identifiable autoantibodies while largely
retaining its core characteristics. Although it is not included as a separate entity
in the European League Against Rheumatism/American College of Rheumatology's classification
of inflammatory myopathies,[1] Connors et al,[4] Solomon et al,[5] and Lega et al[6] have proposed alternative classification criteria to assist in identifying the disease.
Many patients afflicted with ASyS experience significant pulmonary involvement either
in isolation or in combination with other organs. This review outlines the common
features of ASyS focusing on the pulmonary manifestations, their appropriate management,
and outcomes.
Epidemiology
IIMs are generally rare,[7] with ASyS considered even more uncommon. But true prevalence of ASyS is affected
by the slow discovery of antisynthetase antibodies (ASAs)[8] and the performance limitations between assays[9] resulting in misclassifying some patients with ASyS into dermatomyositis (DM) or
polymyositis (PM). Finally, many studies of prevalence depended on muscle biopsies
for diagnosis of IIM,[10]
[11]
[12] excluding in the process patients with amyopathic disease.[13]
Taking all these factors into consideration, a comprehensive international registry
highlighted ASyS as the third most common IIM. Seventeen percent of the total 3,002
included individuals were classified as ASyS. Intriguingly, a large number of patients
with AsyS were reclassified from other IIM upon retrospective review and application
of Connors' proposed criteria. In a more recent update of the same registry, there
was a larger proportion of ASyS that was closer to 20%.[14] In another large cohort of 1,113 IIM patients from China, 21% were found to have
ASyS,[15] whereas 22% in a Canadian cohort had ASA.[16] A similar 19.4% proportion of ASyS was seen within another cohort from China.[17] A lower 14.1% of IIM had ASyS,[18] in an ethnically diverse study from a large U.S. myositis center. An even lower
proportion of 11.1% were observed to have ASyS when exclusively relying on biopsies
for the diagnosis of IIM.[19] Orphanet estimates that a quarter of all IIM have ASyS and predicts a prevalence
of around 1/25,000–33,000.[20]
ASyS more frequently affects females, with a ratio of approximately 2–3:1.[15]
[17]
[18]
[21]
[22] Although anti-Jo-1 antibody remains the most common ASA, regional or ethnic differences
may exist. Patients in East Asia and those with African heritage show higher levels
of non-anti-Jo-1 positivity.[15]
[17]
[19]
[23]
[24]
[25]
[26] Disease onset is often between the fourth and fifth decades of life. It is unclear
whether men may have a later disease onset.[27]
Pathogenesis
The precise underlying mechanisms leading to immune-mediated disease in IIMs are yet
to be elucidated. However, the distinct mechanism between the different forms of IIM
has been supported by the difference in their pathological picture. In ASyS, presence
of myonuclear actin aggregation, intranuclear rod formation, and presence of atrophic
fibers and perimysial fragmentation[28] are unique. Myxovirus resistance A expression, an interferon-inducible protein recognized
for its high specificity as a marker for DM (98% specificity), is not displayed in
ASyS.[29] These pathological distinctions have aided in the classification of ASyS as a separate
entity[30] and provided insights into a differing pathogenesis.
Our current understanding of ASyS like other autoimmune disorders suggests a dysfunction
in the innate and acquired immune system that is probably triggered by an environmental
event. This leads to a selection of immune cells that recognize self-antigens leading
to autoimmunity. This selection is probably favored under certain conditions (e.g.,
genetic predisposition, estrogen level, microbiome)[31]
[32]
[33] leading to auto-antigen production.[34] It is widely postulated that the lungs may be the origin of the disease pathogenesis.
Observational studies have noted that there is higher incidence of respiratory tract
disease or environmental irritant exposure preceding the manifestation of myositis.[35]
[36] The resultant epithelial stress or death imposed by previous exposures is thought
to cause microparticulate release that includes cytoplasmic and nuclear materials
that likely include cytoplasmic ARSs. These ARSs trigger the immune system leading
to the development of ASA.[37] While B cells are responsible for antibody production in these patients, activated
CD4+ T cells appear integral in their generation.[38]
[39]
[40]
The subsequent generation of the disease phenotype is thought to be at least partially
mediated by ASA causing the loss of ARS function. Most of the ARSs have pleiotropic
functions and can affect both immune and nonimmune processes. For example, histidyl-tRNA-synthetase
(the target of anti-Jo-1) has antioxidant, anti-inflammatory, and antisecretory properties
while also involved in cellular adhesion mechanisms and activation of various immune
cell subtypes.[41]
[42]
[43]
[44] The generation of specific ASA has been shown to subsequently lead to muscle inflammation
and lymphocytic predominant lung infiltrates in murine models.[37] These immune changes likely ensue in a genetically predisposed host. Single nucleotide
polymorphisms in HLA-B and HLA-DR have been shown to have the strongest association
with ASyS.[45]
[46]
[47]
[48] Despite the ubiquitous presence of ARS, the tropism of ASA to certain organs is
poorly understood. Since immune dysfunction is thought to be triggered in the lung,
its involvement is present in the majority of patients.
Clinical Features
There are similarities in the presentation of ASyS: including some combination of
fever, myositis, ILD, inflammatory polyarthritis, Raynaud's phenomenon (RP) or mechanic's
hand (MH). The heterogeneity in manifestations is thought to be largely driven by
the different ASAs.[49] The classic triad of ILD, myositis, and arthritis has only been seen in 15% of patients
included in a large international cohort,[22] and a similar 14% in a smaller ILD-specific cohort from China.[50] The proportion of patients with the classic triad rose to 44% during follow-up,[22] highlighting the evolving nature of ASyS.
Muscle Disease
Muscular involvement in ASyS can occur in the form of myalgia and/or weakness, with
a subset of patients also suffering from dysphagia.[19]
[51] The prevalence of muscle weakness and myalgia varies significantly across different
cohorts of ASyS, ranging from 41 to 100% for muscle weakness and 30.4 to 88.9% for
myalgia,[14]
[15]
[17]
[19]
[22]
[52]
[53]
[54]
[55] while primarily involving the proximal muscles.[19] The presence of anti-OJ appears to confer more severe muscle involvement, while
anti-PL-12 has milder forms of muscle disease.[56] Despite this, anti-Jo-1 positivity remains the highest predictor for muscle involvement.[22] Respiratory muscle involvement has also been documented to occur in approximately
8%.[19]
Joint Disease
Arthritis and arthralgia are common in patients with ASyS. The prevalence may vary
depending on the studied cohort and the underlying ASA profile. In smaller studies
joint involvement ranged between 12[18] and 88%.[57] However, when examining larger patient samples, the frequency is closer to 65%.[22]
[53]
[54]
[55] Individuals with anti-Jo-1 antibodies are more likely to have joint involvement
compared with others.[22] Joint disease is often symmetrical, polyarticular, and predominantly affects the
hands and wrists. While predominantly nonerosive in nature, some patients may develop
erosive arthritis with concomitant seropositivity for anti-rheumatoid factor (anti-RF)
antibody or anti-citrullinated protein (anti-CCP) antibody, potentially causing misclassification
as rheumatoid arthritis.[53]
[58]
[59]
[60] Erosive arthritis has also been documented in up to 35%, even in the absence of
anti- RF antibody or anti-CCP antibody.[61] A substantial number of patients also exhibit oligoarthritis or asymmetrical arthritis,
with more than 70% of anti-OJ patients presenting with such features.[22]
Cutaneous
RP is a significant manifestation of ASyS and has been reported to occur in approximately
39% of patients in large international registries.[14]
[22] RP has also been shown to be the initial symptom in patients with anti-Jo-1 profiles
and may predispose to an arthritis phenotype.[53]
[54] Another hallmark sign of ASyS is MH, a nonpruritic hyperkeratotic, fissured, scaly,
eruptions mainly affect the palms and radial aspects of the hands and index finger.
These occur in nearly 40% of ASyS although reported more variably in smaller sized
studies. More importantly, MH often improves with treatment and can serve as a sign
of uncontrolled disease or a flare that may include the lungs.[62] Additionally, while MH is an important feature of ASyS, it is not pathognomonic
and can be present in DM.[14] Conversely, cutaneous manifestations of DM including Gottron's sign, heliotrope
rash, shawl sign, periungual erythema, digit ulceration, calcinosis, and the holster
sign can be observed in ASyS in varying frequencies, reaching up to 44%.[14]
[17]
[51] Another cutaneous finding that resembles MH is hiker's feet ([Fig. 1]) with similar features involving the toes and feet and often occurring in conjunction
with MH.[63]
Fig. 1 Extrapulmonary manifestations of ASyS. (A) V-neck rash. (B) Gottron's papules. (C) Gottron's papules. (D) Mechanic's hand. (E) Mechanic's feet. (F) Calcinosis. (G) Ragged cuticles and periungual erythema. ASyS, antisynthetase syndrome.
Other Features
Fever affects over one-third of patients throughout their clinical course.[19]
[22]
[51]
[53] There is a suggestion that patients positive for anti-EJ or anti-PL-12 are more
likely to suffer from fever, but these findings have not been replicated elsewhere.[15]
[22] Individuals may additionally suffer from sicca symptoms, reported to affect up to
33%[25] and possibly associate with anti-KS antibody positivity.[64] Cardiac involvement has also been detected in patients with ASyS. In the most recent
published cohort, this accounted for 7% of a 649 patient registry.[14] Cardiovascular manifestations include myocarditis, arrhythmias, elevated cardiac
enzymes in the absence of a coronary insult, pericarditis, and pericardial effusion.[49]
Pulmonary Manifestations
Interstitial Lung Disease
ILD stands out as one of the most important and characteristic feature of ASyS. Findings
from large patient cohorts and registries indicate that ASyS-associated ILD (ASyS-ILD)
occurs in up to 68 to 94%,[14]
[17]
[22]
[53]
[55] affirming the high prevalence observed in smaller studies.[25]
[65]
[66] In patients with anti-Jo-1 antibodies, the most common form of ASyS, 29 to 84% have
been noted to have lung disease across a wide range of studies.[49] However, ILD rates appear to be higher in anti-EJ positive patients noted as 90
to 100%.[17] Importantly, despite anti-EJ positive patients appearing to have the highest prevalence
of ILD, previous reports suggested that anti-PL-7- and PL-12-positive patients more
commonly have ILD.[18]
[67] This assertion has been somewhat challenged by data from the international study
of 828 ASyS patients conducted by the American and European Network of Antisynthetase
Syndrome (AENEAS). The study demonstrated that at disease onset, 69% of anti-PL-12
and 73.7% of anti-EJ positive patients had ILD, and both percentages were significantly
higher than in patients with anti-Jo-1 antibodies (p = 0.001 and p = 0.005, respectively). This suggests that anti-EJ-positive patients may have a more
prominent association with ILD. Nevertheless, in a group of 233 patients with anti-Jo-1,
anti-PL7, and anti-PL12 antibodies, hierarchical cluster analysis revealed that patients
positive for anti-PL7 and anti-PL12 exhibited a more lung-restricted phenotype correlating
with the higher occurrence of lung involvement in these two groups.[55] Together, these data support the notion that patients with anti-PL7, PL-12, and
EJ antibodies present a phenotype characterized by high pulmonary involvement. Moreover,
ethnicity may play a role in the development of lung disease in ASyS. Black individuals
are more likely to have non-Jo 1 serology[18]
[68] and when compared with white patients, had worse ILD with an 18% lower forced vital
capacity (FVC; p < 0.001) and 12% lower diffusing capacity of the lungs for carbon monoxide (DLCO;
p < 0.01), independent of the antibody status.[18]
While some may have subclinical ILD, patients often present with cough or dyspnea
on exertion.[53] Although many individuals with ASyS present with a gradual onset of symptoms, a
substantial number manifest with acute-onset ILD across all antibody subtypes. Close
to half the patients from a 32-patient study in France[69] required supplementary oxygen less than 9 weeks from symptom onset. In total, 21%
of patients from another small study who were seropositive for anti-Jo-1 were additionally
classified to have acute onset of ILD,[52] while a similar percentage was seen in a 234 patient Chinese cohort with a more
expansive ASA profile.[15] Patients from the large AENEAS study showed that 20 out of 38 (74.1%) anti-EJ patients
had acute onset of ILD defined as onset and worsening of symptoms within a 4- to 6-week
time frame. Strikingly, the rate was 37.5 to 48.3% in the other antibody groups (anti-Jo-1,
anti-PL7, andti-PL12, and anti-OJ were available).[22] Yet, there are contrasting data showing a much lower 9.6% rate of acute-onset ILD
in a Spanish cohort of 148 anti-Jo-1-positive patients.[53] Similarly, a Chinese study demonstrated a comparable low rate of 8.9% of 124 patients
with a diverse antibody profile that developed acute ILD despite their more liberal
definition (worsening dyspnea and hypoxemia within 3 months of symptom onset).[17] Certainly, while the data may be conflicting, there is substantial evidence supporting
the occurrence of acute ILD. Analysis of bronchoalveolar lavage fluid in patients
with acute ILD demonstrated a neutrophil-predominant cell differential, significantly
higher than their nonacute counterparts (66.9% vs. 29.1% respectively, p = 0.004).[69] This may suggest an element acute lung injury (ALI).
Co-existence of anti-Ro-52 antibodies has been shown by several investigators to associate
with worse lung disease in ASyS.[17]
[23]
[70]
[71]
[72]
[73]
[74] However, this has not been universally observed especially in larger more diverse
populations.[18]
[53]
[55]
[75] Based on these discrepant reports, it is unclear to what degree anti-Ro-52 contributes
to worse pulmonary manifestations in ASyS.
A restrictive physiology is typically seen in ASyS. In the assessment of FVC in 96
subjects with anti-Jo-1-positive antibodies, a mild restrictive physiology was observed
with a mean of 65.7% with a corresponding mean total lung capacity (TLC) of 67.2%
predicted.[76] Additionally, DLCO was moderately reduced, with a mean of 56.3% predicted. In another
study with multiple ASA-positive patients, the baseline FVC and DLCO across the different
ASA groups was mild to moderately reduced at 63.3 to 71.2% predicted and 57.6 to 68%
predicted respectively with no significant differences.[77] In cases where there is a more significant reduction in FVC, TLC, or vital capacity
than would be expected based on radiological disease involvement, respiratory muscle
weakness should be considered.[9] Measurement of the maximum inspiratory pressure, the maximal sniff nasal inspiratory
pressure, and the maximum expiratory pressure can help obtain more insight into the
strength of different respiratory muscle groups.[78]
[79]
Imaging
High-resolution computed tomography (HRCT) imaging of individuals with ASyS is essential
for characterization and assessment of disease burden. Changes observed in ASyS-ILD
include ground glass opacities (GGOs), air space opacities, traction bronchiectasis,
reticulation, interlobular septal thickening, and volume loss indicative of ILD ([Fig. 2]). These changes are often seen in the lower lobes or sometimes diffusely, with peripheral
or peribronchovascular predominance. The imaging findings correspond to a particular
radiographic pattern in most cases. In an analysis of 33 patients with anti-Jo-1,
anti-PL7, and anti-PL12 antibodies, all demonstrated GGOs at diagnosis with almost
half of the patients having concomitant consolidative changes.[80] A nonspecific interstitial pneumonia (NSIP) pattern was most common (45%), while
organizing pneumonia (OP) or a mixed NSIP-OP CT pattern occurred in 21 and 24%, respectively.
Waseda et al reviewed retrospectively 64 patients with ASyS-ILD in patients with anti-EJ,
anti-KS, and anti-OJ.[81] GGOs dominated HRCT changes in tandem with reticulations and interlobular septal
thickening. Distribution of changes were almost exclusively peripheral and lower zone
predominant. NSIP and OP were the principal radiographic patterns occurring in 55.6
and 41.2% of patients, respectively. In another review focusing on 51 anti-EJ-positive
patients with ILD, GGOs were again universally observed.[82] Changes consistent with NSIP or OP were again primarily observed suggesting no clear
difference in presentation of ASyS-ILD across the different antibody profiles. Whereas
radiographically, NSIP is most frequently observed in ASyS, Zhan et al reported on
108 patients where OP appeared more commonly than NSIP representing 49.1%.[77] Liu et al[82] also found that in patients with anti-EJ-positive antibodies (n = 23, 78.3%) had imaging consistent with OP.
Fig. 2 Different CT patterns in patients with ASyS. (A) Ground glass opacities, reticular thickening and subpleural sparing consistent with
a NSIP in a patient with anti-PL12 serology. (B) Ground glass opacities, reticular thickening, subpleural sparing, and traction bronchiectasis
consistent with a fibrotic NSIP in a patient with anti-PL7 serology. (C) Interstitial infiltrates with ground glass opacities, alveolar nodules, and subpleural
bands consistent with an OP in a patient with anti-Jo1 serology. (D) Diffuse subpleural reticulation, fibrosis, traction bronchiectasis, and honeycombing
consistent with an UIP pattern in a patient with anti-Jo1 serology. ASyS, antisynthetase
syndrome; CT, computed tomography; OP, organizing pneumonia; NSIP, nonspecific interstitial
pneumonia; UIP, usual interstitial pneumonia.
While NSIP, OP, or an NSIP/OP overlap patterns are most frequently observed, other
changes have also been described. Usual interstitial pneumonia (UIP) has been observed
in a minority of patients with ASyS. Zamora et al found that 13% of their anti-Jo-1
patients demonstrated a possible UIP pattern on imaging,[76] but these changes have been seen at rates of 3.7% or less in other retrospective
analysis.[77]
[81]
[82] Notably, a proportion of patients with UIP may demonstrate anterior upper lobe,
straight edge, or/and an exuberant honeycombing sign.[83] Other investigators have reported on imaging consistent with acute interstitial
pneumonia (AIP), but this represents a very small percentage of patients. In a multicenter
retrospective analysis from the United Kingdom, only 1 out of 76 patients with ASyS
had imaging consistent with diffuse alveolar damage (DAD), corresponding to AIP.[84] However, a smaller study noted a higher percentage of patients with AIP (18%).[85] Other reports have been equally variable with AIP pattern in 0 to 6% of their cohorts.[86]
[87]
[88]
[89]
[90] More conclusively, in a systematic review and meta-analysis involving 306 patients
with available radiographic information, NSIP was most common (67%), followed by OP
(24%) and UIP (9%), while AIP represented 1% and 3% remained unclassifiable.[91]
Histopathology
Radiographically, NSIP and OP patterns dominate, though histological changes do not
completely correspond. It is important to stress, however, that histological evaluation
of patients with ASyS is limited due to factors such as the underlying severity of
illness at baseline, concerns about disease flare with biopsy, and perceived lack
of benefit or change in management obtained from a biopsy. In a group of 41 patients
with ASyS for whom 18 surgical lung biopsy results were available, there was an equal
distribution of OP, NSIP, and UIP histological findings.[68] The mean time interval between ILD diagnosis and undergoing a biopsy was 15 months,
a factor that may affect tissue evolutionary changes. In a case series of 39 subjects
who were anti-Jo-1 positive with biopsy data, OP and NSIP (26 and 23% of cases, respectively)
were the most common findings with UIP and DAD representing close to 15% of the cases
each.[76] In an autopsy-focused histological assessment of 22 patients with anti-Jo-1 serology,
there was a predominance of DAD (55%) and UIP (45%) changes with a minority having
a NSIP subtype (14%) (some had multiple histological patterns).[66] These findings should be interpreted with caution given the postmortem nature of
the study.
Looking at ASA groups separately, in 12 patients with anti-PL12 serology for which
lung histology was available, the majority showed a UIP pattern (8/12, 66.7%) with
an equal remaining number for NSIP and OP (2 each, 16.7% each).[92] In other reports that included smaller numbers of PL-12-positive patients, UIP was
seen in 60%, OP and NSIP in 20% each (5 total patients),[68] while NSIP was seen in all the patients included in another study (2 total patients).[93] For PL-7 positive patients, one study showed equal distribution of NSIP, OP, and
UIP (3 total patients).[68] Another demonstrated UIP in 50%, OP in 25%, and NSIP in 12.5%[94]; while a total of 5 biopsies available in one report showed UIP in 60%, and both
OP and NSIP in 20% each.[95] In a group of 12 patients with anti-EJ, biopsy results that were obtained in a median
interval of 28 days from the date of the HRCT, 75% had NSIP while the remainder were
unclassifiable.[96] A smaller cohort of four patient positive for anti-EJ also echoed these findings
with 75% exhibiting NSIP while the remainder had UIP.[97] Among four patients with anti-EJ, half of them had DAD while the remainder had UIP.[98] In the largest cohort of anti-KS positive patients, 14 surgical lung biopsy results
were available; 85.7% had NSIP, whereas the remaining 14.3% were unclassifiable.[99] Interestingly, the authors categorized any signs of ALI on biopsy as unclassifiable,
arguing for the possibility of higher rates of DAD. In contrast, surgical lung biopsies
from five patients exhibited predominantly UIP changes (80%) with the final patient
showing an OP pattern.[100] Limited reports are available for histopathological findings in anti-OJ-positive
patients. However, in a study from Japan, surgical lung biopsies were available in
3, showing an equal distribution of NSIP, UIP, and COP.[101] Finally, no biopsy results have been reported for other rare ASA profiles including
anti-Zo and anti-YRS.
Flashner et al collated all the reported histopathological reports of individuals
with ASA-associated ILD allowing for a better overview of pathological patterns in
ASyS.[102] NSIP remained the most prominent manifestation for patients with anti-Jo-1, anti-KS,
and anti-EJ. Anti-PL12 patients had significantly more UIP pattern than other antibody
profiles, and both anti-KS and anti-EJ patients were statistically least likely to
have changes consistent with OP. Anti-EJ and anti-Jo-1 patients had the largest proportion
of histological ALI changes. Overall, NSIP remained the most common pathological finding
accounting for 41%, UIP for 24%, OP for 19%, and ALI representing 13.5%. This contrasts
with the radiographic findings where NSIP was more frequently seen (67%), OP (24%)
was more common than UIP (9%), and AIP was only described in 1%. Part of this discrepancy
may be explained by the inclusion of multiple pathology patterns on each biopsy report,
and the more granular detail that arises from microscopic assessment of tissue biopsies.
The biopsy discrepancy from imaging findings may additionally be driven by the mode
of biopsy (surgical vs. transbronchial), the interval between the initial HRCT, and/or
the motivation for biopsy acquisition (e.g., worsening clinical picture) that may
predispose to more ALI pathologic changes.
Pulmonary Vascular Disease
Pulmonary Vascular Disease
Pulmonary vascular involvement in the form of pulmonary hypertension (PH) may be difficult
to categorize due to the recent change in the diagnostic parameter that lowered the
threshold of PH diagnosis.[103] Regardless, PH in ASyS is often attributed to group 3 disease owing to the extensive
lung involvement in many patients and limited reports of group 1 (connective tissue
disease [CTD]-related) disease exists.[104]
[105]
[106]
[107]
[108] In reports where pulmonary arterial hypertension (PAH) is diagnosed, this is often
due to either limited parenchymal disease and/or hypoxemia, or when the PH is out
of proportion to the degree of ILD. The prevalence of PH in ASyS can be overestimated
when patients are solely screened with transthoracic echocardiography (TTE), as demonstrated
by Abel et al.[104] In their cohort, there was TTE evidence of PH in 23%. Of their cohort, 16 of 21
were confirmed on right heart catheterization (RHC). Overall, most large cohorts that
reported PH based on RHC estimated variable prevalence of 7.9 to 20%.[54]
[104]
[109]
[110] Reports of successful management of PH-associated ASyS have been inconsistent with
several case reports documenting improvement in symptoms and hemodynamics upon treatment
with PAH-specific therapies.[104]
[111] However, in the largest collection of patients with RHC diagnosed precapillary PH,
where 19 patients were started on PAH-specific therapy, improvement was not seen.[111]
Many patients with a diagnosis of PH have additional serology for anti-Ro-52. Whether
this is an associated marker for PH development or related to worse pulmonary disease
that is reflected in a higher rate of group 3 PH is difficult to discern from the
available literature. Overall, while there is clear evidence for precapillary PH in
patients with ASyS, it is unclear which individuals may suffer from PAH (group 1 disease).
Therefore, better characterization and patient selection may be necessary to establish
benefits from PAH-specific therapy.
Pleural Disease
Pleural involvement is rare in ASyS and should prompt investigation to rule other
causes. Nevertheless, there have been a handful of reports describing primarily pleural
effusions developing in patients with ASS. A 69-year-old female who presented with
fever and left-sided eosinophilic pleural effusion that was unresponsive to antibiotics[112] later developed other signs of ASyS and was positive for PL-7 antibody. Her pleural
biopsy showed evidence of intercostal muscle myositis and pleuritis requiring immunosuppression
to control her disease. Another young female with anti-Jo-1-positive serology presented
with OP but quickly progressed without treatment to arthralgia, profound weakness,
MH, and bilateral pleural effusion.[113] The pleural fluid was exudative and lymphocytic but sterile. Her effusions resolved
with immunosuppression. Other case reports show a similar sterile exudative pleural
effusion that resolves when the disease activity is controlled, suggesting an element
of ASyS-mediated pleuritis.[114]
[115]
[116]
[117] Interestingly, in an extensive retrospective analysis for evidence of serositis
in ASyS, 93 patients were isolated.[118] Pleural effusions were present in 44% of patients, 75% of which were bilateral.
Patients with PL-12 antibodies were statistically more likely to develop pleural effusions
(p = 0.003). This study demonstrated a higher rate of pleural effusions in ASyS than
reported elsewhere, and may be limited by its retrospective nature, ability to attribute
the pleural effusions to ASyS, and the lack of exclusion of other etiologies for pleural
effusions. In conclusion, pleural involvement in ASS remains limited in large registry
databases but can occur in select patients.
Mode of Presentation
The initial association of anti-Jo-1 antibody with myositis, ILD and MH has led to
the description of a triad presentation in ASyS. However, the presentation of ASyS
can be widely variable. In those who lack the triad, either isolated organ involvement
or a combination of other symptoms may constitute their initial presentation. In a
meta-analysis from 2014, individuals with ASA often presented with arthralgia (62%)
or ILD (72%).[119] It is unsurprising that the pleiotropic presentation of ASyS may be at least partially
driven by the specific ASAs. In a large American and European cohort of patients,[22] the mode of presentation was slightly different according to the antibody profile.
For individuals with anti-Jo-1, isolated arthralgia was the main presentation in 22%,
whereas ILD predominated the initial presentation in those with anti-PL-7 (36%), anti-
PL-12 (43%), and anti-EJ (39%). This emphasizes the necessity for pulmonologists to
maintain a high index of suspicion when evaluating patients with ILD. Interestingly,
presentations with isolated myositis (10–17%), arthritis (11–23%), as well as a combination
of arthritis + myositis (3–13%), or arthritis + ILD (6–24%) were not statistically
different across the remainder of antibody profiles in the same cohort. Overall, isolated
organ involvement at presentation occurred in 64% of the study participants. Antibody
profiling additionally predicted the likelihood of progression to include lung disease
in the same study.[22] This was predominantly observed in patients with anti-Jo-1, where 63% developed
new-onset ILD during follow-up, and a comparable 60% increase was noted in patients
with anti-EJ. New ILD was seen in approximately 50% for both anti-PL-17 and anti-PL12,
but only in 30% of anti-OJ. Therefore, while ILD remains as a major component of ASyS,
it can occur as a primary or subsequent presentation.
Antisynthetase Antibodies
tRNA synthetases are a family of enzymes found in either the cytosol or mitochondria
and are involved in cellular protein synthesis.[120] In total, there are 20 tRNA synthetases, with autoantibodies discovered against
many of them. However, only 10 (originally 8 with recently discovered anti-Ly[121] and anti-VRS[122]) have been directly linked with ASyS. Other ASA such as anti-SC and anti-WARS have
been linked to other autoimmune diseases.[123]
[124]
[125] Anti-Jo-1 was first discovered in 1983,[126] followed quickly by others and later linking them to autoimmunity and myositis.
While most tRNA synthetases can function independently, eight of them require binding
together in a complex known as the multi-tRNA synthetase complex.[51] Anti-OJ antibodies primarily target the isoleucyl-tRNA synthetase component of this
complex.[51]
Anti-Jo-1 antibodies are the most common ASA amongst patients with ASyS although its
prevalence varies according to the cohort. Given that anti-Jo-1 is more readily available
for testing compared with other ASAs, this may lead to disparate detection rates compared
with other ASA. ASyS may behave differently according to the specific ASA; clinical
distinctions amongst various ASAs are outlined in [Table 1]. Moreover, antibody levels can fluctuate through the disease course depending on
disease activity and in response to treatment.[127]
[128]
[129]
Table 1
Antisynthetase antibodies and prevalence
|
Antisynthetase antibody
|
tRNA synthetase auto-antigen
|
Prevalence (%)[14]
[15]
[16]
[17]
[18]
[19]
[22]
[23]
[24]
[25]
[26]
[27]
[50]
[77]
[88]
[89]
[250]
[256]
[257]
[259]
[260]
[263]
[264]
[265]
[266]
[267]
[268]
[269]
|
Features
|
|
Anti-Jo1
|
Histidyl
|
60–65
|
Often have classic triad
|
|
Anti-PL7
|
Theronyl
|
15–20
|
More severe ILD, higher rates of esophageal involvement
|
|
Anti-PL12
|
Alanyl
|
10–15
|
More severe ILD, higher rates of esophageal involvement, lower myositis rates, worse
survival
|
|
Anti-OJ
|
Components of MSC/isoleucyl
|
1–5
|
Possibly affects older patients, lower rates of arthritis, mainly asymmetric arthritis.[22] May be associated with malignancy.[270]
|
|
Anti-EJ
|
Glycyl
|
5–10
|
More acute onset ILD, low rates of arthritis at presentation, worse survival
|
|
Anti-KS
|
Asparaginyl
|
<1
|
Mainly ILD, low rates of arthritis, myositis rare
|
|
Anti-Zo
|
Phenylalanyl
|
<1
|
Often have classic triad
|
|
Anti-YRS/Ha
|
Tyrosyl
|
<1
|
Rare, no distinct features
|
|
Anti-Ly
|
Cysteinyl
|
<1
|
Rare, no distinct features
|
|
Anti-VRS
|
Valyl
|
<1
|
Rare, no distinct features
|
Abbreviations: ILD, interstitial lung disease; MSC, multienzyme synthetase complex.
Diagnosis
Diagnosis of ASyS is made using one of the proposed criteria outlined in [Table 2]. Given the heterogenous presentation of ASyS, its evolving nature, and overlapping
symptoms with other disease, the performance of specific criteria will differ. There
is a lack of evidence in the literature of how these differing criteria perform. All
the criteria currently available include the presence of ASA as a prerequisite for
the diagnosis but differ in the number and type of additional symptoms required. Currently,
there are no existing data-driven or validated classification criteria for ASyS. A
recent systematic review revealed numerous variabilities in defining ASyS across the
literature, coupled with a lack of sensitivity and specificity of its clinical variables
including muscle biopsy findings.[130]
Table 2
Diagnostic criteria for antisynthetase syndrome
|
Connors[4]
|
Solomon[5]
|
Lega (revised Connors)[6]
|
|
Anti-aminoacyl-tRNA synthetase autoantibody positivity plus one among:
• Myositis (Bohan and Peter's criteria)
• ILD by ATS criteria
• Arthritis (clinic, X-rays, self-report)
• Unexplained fever
• Raynaud's phenomenon
• Mechanic's hands
|
Anti-aminoacyl-tRNA synthetase autoantibody positivity
plus (2 major criteria or 1 major plus 2 minor criteria)
Major criteria:
• Myositis (Bohan and Peter's criteria)
• ILD by ATS criteria
Minor criteria:
• Arthritis
• Raynaud's phenomenon
• Mechanic's hands
|
Anti-aminoacyl-tRNA synthetase autoantibody positivity plus one among:
• Myositis (overt or hypomyopathic)
• ILD by ATS criteria
• Arthritis or arthralgia
Or two among:
• Unexplained fever
• Raynaud's phenomenon
• Mechanic's hands
|
Abbreviations: ATS, American Thoracic Society; ILD, interstitial lung disease.
In our practice, we have a high index of suspicion for ASyS even in the absence of
extrapulmonary symptoms, especially in patients with an NSIP, OP, or NSIP-OP overlap
pattern of ILD; and routinely screen for ASA. Despite the above-mentioned limitations,
we rely on Connor's criteria because of our long-standing experience with it and its
relative simplicity. We therefore seldom send patients for lung biopsies. We prefer
a comprehensive myositis panel that utilizes multiple different assays for antibody
detection including immunoprecipitation (considered the gold standard).[131] We also screen for other organ involvement when indicated (e.g., magnetic resonance
imaging for myositis[132]
[133]).
Management of Pulmonary Manifestations
Management of Pulmonary Manifestations
Much of the management of ASyS-ILD is extrapolated from care established in IIM or
other CTD-associated ILD (CTD-ILD). Therefore, the mainstay of treatment is immunosuppression.
The use of immunosuppressive therapies has shown to reduce the pulmonary disease burden
reflected by functional improvements in IIM-associated ILD (IIM-ILD).[134]
Treatment for ASyS-ILD can be challenging with presentations varying from asymptomatic,
to chronically progressive, or rapidly progressive ILD (RP-ILD). In patients with
significantly clinical ILD, disease severity can range from mild to life-threatening.
Additionally, patients with stable lung disease can have episodes of acute exacerbations
that can be unpredictable necessitating alteration in their therapy. Differences in
medication pharmacokinetics are also important to keep in mind. Glucocorticoids have
a pivotal role in initial therapy, but use of steroid-sparing agents is necessary
to mitigate steroid side effects. mycophenolate mofetil (MMF) and azathioprine (AZA)
take longer time to reach their maximum effect and therefore appropriate for mild–moderate
ASyS-ILD, whereas tacro and intravenous immunoglobulin (IVIG) have a more rapid onset
making them more appealing for severe disease and acute exacerbations. Some patients
also exhibit resistant disease despite therapy with corticosteroids and two immunosuppressive
agents forcing the trial of other therapies that include rituximab (RTX) and IVIG.
An algorithm for management is presented in [Fig. 3].
Fig. 3 Algorithm suggesting management for antisynthetase associated ILD (ASyS-ILD) according
to severity of disease. Decision for the use of chronic immunosuppression and agent
of choice is governed by several variables including disease severity, response to
initial therapy, familiarity of physician with medication, co-morbidities, and disease
course. AZA, azathioprine; ECMO, extracorporeal membrane oxygenation; IVIG, IV immunoglobulin;
MMF, mycophenolate; PFT, pulmonary function test; PLEX, plasma exchange; RTX, rituximab;
TAC, tacrolimus. Adapted from Hallowell & Danoff.[145]
Nonpharmacological treatment also plays a crucial role in the care of patients with
ASyS-ILD. Supportive measures include supplemental oxygen therapy as well as adequate
prevention of infections. With advances in medical practices, patients with acute
exacerbations may benefit from a tailored approach when hospitalized in the intensive
care unit (ICU). Finally, lung transplantation may be an option for some patients
with ASyS-ILD unresponsive to therapy and should be considered on a case-by-case basis.
Immunosuppression
Corticosteroids
Corticosteroids are the backbone of initial therapy in ASyS-ILD. Much of the data
for their use stem from observational studies in patients with IIM that have shown
either improvement or stability of disease with their use.[135]
[136]
[137] Specifically in ASyS-ILD, 37 patients classified as dermatomyositis (DM)/polymyositis
(PM) with concurrent presence of ASA had improvement in the pulmonary function tests
(PFTs) and/or HRCT findings with corticosteroids being part of their management.[138] In other case series, 28 (42%) of 66 patients[65] and 6 (43%) of 14 patients with anti-PL-7 positivity[95] showed favorable response with corticosteroid therapy alone. There are currently
no available indicators that can predict steroid responsiveness in ASyS-ILD. The literature
suggests that patients with a more prominent inflammatory component in NSIP or OP
pattern may exhibit more favorable responses to corticosteroids.[138]
[139]
[140]
[141]
Consistent with expert opinion, we recommend the initiation of prednisone at 0.5 to
1 mg/kg/day depending on disease severity with monitoring for improvement of symptoms.[142]
[143]
[144]
[145] For patients with severe disease, RP-ILD, acute exacerbations, or impending respiratory
failure, we administer high-dose intravenous methylprednisolone 1 g daily for 3 days.
In these patients we also simultaneously initiate a second immunosuppressive agent
with a rapid onset, such as IVIG before transitioning to oral prednisone 1 mg/kg/day.
Lastly, we include a steroid sparing agent.
We favor maintaining the steroid therapy for 1 month and if improvements are observed
in symptoms, PFTs, and imaging, prednisone is then tapered down to 40 mg/day. Subsequently,
we decrease prednisone by 25% every 2 to 4 weeks until reaching a dose of 20 mg/day,
followed by a slower taper of 2.5 mg/day every 2 weeks. Based on our experience, we
have noted severe or refractory ILD flares during tapering of glucocorticoids. Therefore,
we maintain the prednisone dose at approximately 5 to 10 mg/day while continuing the
steroid sparing agent until improvement or stabilization of symptoms, lung function
tests, and CT abnormalities have plateaued. Once stabilized on a steroid sparing agent,
prednisone can be weaned off with care to identify any evidence of symptomatic worsening
or flare and a low threshold to escalate the steroid dose in the setting. Prophylaxis
for Pneumocystis jirovecii is strongly recommended in ASyS-ILD patients.
Steroid Sparing Agents
Purine Synthesis Inhibitors—Azathioprine and Mycophenolate Mofetil
AZA, a prodrug, functions primarily via its conversion into 6-mercaptopurine to interfere
with DNA and RNA synthesis in leukocytes thereby limiting their proliferation and
effector function.[146] The metabolism of 6-mercaptopurine depends on thiopurine methyltransferase (TPMT).
Patients can undergo screening for TPMT deficiency, as it may result in increased
AZA toxicity. MMF, also a prodrug, inhibits the formation of de novo guanine nucleotides,
necessary for the generation of DNA; this leads to the inhibition of lymphocyte proliferation,
leukocyte recruitment, and cytokine production.[147]
[148] No direct comparison of these two drugs exists, but their efficacy in controlling
disease and improving lung function has largely been established from observational
studies. In an analysis of 66 patients with ASyS-ILD, 20 subjects dependent on AZA
or MMF for ILD improvement.[65] In a larger retrospective review of 110 patients with myositis-related ILD, over
60% had ASA, significant improvements in PFTs, and steroid lowering effect was achieved
with the use of either MMF or AZA.[149]
We start AZA at a dose of 50 mg/day before the dose is increased by 50 mg every 1
to 2 weeks with ongoing monitoring for any blood dyscrasia or liver toxicity until
reaching a dose of 2 to 2.5 mg/kg day (typically not exceeding 200 mg/day). For those
with intermediate TMPT levels, lower doses may be necessary, and we avoid AZA in individuals
with low TMPT levels. We prefer AZA for patients considering conception. We typically
initiate MMF at 500 mg twice daily, aiming for a target dose of 2 to 3 g/day. In some
patients, MMF may not be well-tolerated due to gastrointestinal side effects and can
be substituted with its active metabolite mycophenolic acid.
Calcineurin Inhibitors
Cyclosporin A (CsA), a cyclic peptide, and tacrolimus (TAC), a macrolide antibiotic
bind to a family of cytoplasmic proteins that inhibit calcineurin suppressing cell
mediated and humoral immune responses.[150]
[151] Both CsA and TAC have been shown to be effective steroid sparing agents in the treatment
of ASyS-ILD.[69]
[152]
[153]
[154] In a cohort of 17 anti-Jo-1 positive patients with ILD, CsA was effective at significantly
improving FVC and DLCO, reducing prednisone to a median of 2.5 mg/day, and adequate
control of disease as evident by ILD flares in 75% of patients who had interruptions
in their CsA therapy.[153] TAC is often preferred over CsA due to it being more potent and its perceived greater
efficacy primarily in myositis-associated ILD.[155]
[156] In 13 patients with ASyS-ILD, TAC was successful at significantly improving both
FVC and DLCO values, control of myositis, and significant reductions in corticosteroid
dosing.[157] In a larger retrospective review of 57 ASyS-ILD patients, CsA (n = 31) and TAC (n = 26) were used in all patients and were associated with significant improvement
in pulmonary functions with near normalization of FVC and DLCO.[158] Extrapolating from the myositis literature, early use of calcineurin inhibitors
in the clinical course of ILD has been linked with better survival, encouraging its
earlier incorporation in the treatment plan.[159]
CsA is dosed 2 to 5 mg/kg twice daily while monitoring and maintaining a blood trough
level of 100 to 150 ng/mL. TAC is started at 0.075 mg/kg twice daily with similar
monitoring for blood trough levels. Many studies using TAC for IIM targeted a trough
of 5 to 10 ng/mL.[155]
[157]
[158]
[160]
[161] However, in our practice, we find maintaining a more conservative trough of 3 to
6 ng/mL achieves excellent disease control with a more favorable side-effect profile.
Cyclophosphamide
Cyclophosphamide (CYC) is an alkylating agent that primarily works by cross-linking
DNA strands leading to reduced replication function in lymphocytes. It has been mainly
employed in patients with severe ILD or RP-ILD. In a retrospective analysis of 62
patients with ASyS-ILD, where CYC and RTX were used in 34 and 28 cases respectively,
pulmonary progression free survival (85 and 92%, respectively) and steroid dosing
at 6 months were similar.[162] The authors did note that survival was higher at 2 years in the RTX group (24% CYC
vs. 54% RTX). It should be noted that there was some selection bias in this study,
as patients in the CYC group had significantly lower lung function tests, while those
started on RTX had more refractory disease at baseline. In a meta-analysis of myositis-associated
ILD therapies that included seven studies that used CYC (n = 71 cases),[134] CYC use was least associated with improvement in patients with chronic ILD. Moreover,
in a recently published randomized controlled trial comparing the use of CYC with
RTX in patients with connective tissue-related ILD, there was no differences in FVC
improvement at follow-up although RTX showed a better side-effect profile.[163]
Because of the associated toxicity[164]
[165]
[166]
[167] and the availability of other options with at least comparable efficacy, we do not
routinely treat our patients with CYC. When used for RP-ILD or severe exacerbations,
we favor the intravenous route initially prescribed at 500 to 750 mg/m2 of body surface area (BSA) repeated every 2 to 4 weeks with 20 to 25% dose (suggested
maximum dose of 1 g/m2 BSA) adjustments based on the white blood cell count response to the initial dose.
Rituximab
RTX is a monoclonal antibody that targets anti-CD20+ B cells leading to their depletion
and subsequent immunosuppression. It is often used in combination with other immunosuppressant
agents for refractory disease or during acute exacerbations.[52]
[88] In a cohort of 112 patients with ASyS-ILD, 34 of whom who received RTX for a median
duration of 52 months showed improvements in FVC, DLCO, and imaging by 24, 17, and
34%, respectively.[127] In an open-label phase II trial of RTX in refractory ASyS, 9 out of the 10 treated
patients showed improvement or stabilization of their ILD.[168] Another retrospective study of 25 ASyS-ILD patients showed that stability or improvement
can be achieved with the use of RTX up to 3 years with repeat dosing of RTX,[88] but noted a decline in DLCO in patients who received a one-time dose of RTX. A meta-analysis
RTX treatment demonstrated a 76.6% (95% confidence interval [CI]: 50.4–96.0; 3 studies,
n = 20) improvement rate in IIM-ILD.[134] In a larger meta-analysis with subgroup analysis for ASyS-ILD, RTX was associated
with an improvement rate of 48.1% (95% CI: 0.373–0.620, 5 studies, n = 68), and a stability rate of 43.4% (95% CI: 0.310–0.607, 4 studies, n = 53).[169] Lastly, as mentioned previously, when compared with CYC, RTX performed better in
pulmonary progression-free survival at 2 years.[162]
We typically prescribe RTX at 1 g on days 0 and 14 with another dose at 6 months for
severe ASyS-ILD or in those with an exacerbation. Subsequent repeat dosing every 4
to 6 months is considered on a case-by-case basis. Prior to therapy we advocate for
the assessment of CD19/CD20 B cell counts and serum immunoglobulin levels to help
with possible complications (impaired B cell reconstitution and hypogammaglobulinemia).[170] Similarly, hepatitis status and tuberculosis exposure should be ascertained prior
to treatment and treatment initiated as needed. When possible, we also ensure adequate
vaccinations before starting therapy.
Intravenous Immunoglobulins
IVIG is derived from the pooled immunoglobulins of thousands of healthy donors. IVIG
is used at higher doses (1–2 g/kg divided over 2–5 days) for autoimmune conditions
and is believed to result in immunomodulation through several pathways. These include
blockade of cell surface receptors, neutralization of proinflammatory cytokines, abating
complement and autoantibody-directed cellular damage, and both saturation of the Fc
receptors and modulation of its expression on immune cells.[171] Much of the literature supports the use of IVIG in IIM for extrapulmonary disease.[172]
[173]
[174]
[175] Observational reports also exist, documenting the benefit of IVIG in IIM-ILD.[176]
[177]
[178]
[179] Specifically for ASyS-ILD, a retrospective study of 17 patients treated with IVIG
showed significant improvements in FVC, DLCO, and a reduction in the mean prednisone
dose.[180]
We use IVIG at a dose of 2 g/kg divided over 5 days and repeated monthly. Typically,
we continue IVIG monthly with another immunosuppressant agent for a duration of 6
months but can be extended further in some patients. Due to its perceived rapid onset
of action, we also employ it in RP-ILD and acute exacerbations. Notable side effects
of IVIG can include aseptic meningitis, hemolytic anemia, and thromboembolic disease.
Vigilance is warranted to identify side effects.
Other Therapies
Tofacitinib, a Janus kinase inhibitor, has been beneficial in treating cutaneous manifestations
in refractory DM.[181] Explorations for its use in anti-MDA-5-related ILD[182]
[183] and ASyS-ILD[184]
[185] have been limited and more research is needed. Abatacept, an inhibitor of anti-CD80/CD-86
which prevents T cell activation, was evaluated in a retrospective report of eight
patients with ASyS-ILD. It was able to alleviate symptoms and significantly improve
DLCO.[186] A recent phase 2 trial demonstrated the safety of abatacept, paving the way for
a phase 3 exploration.[187]
Plasmapheresis has been explored as an appealing option for those with critical illness
to allow for immunosuppression and recovery. The overwhelming majority of the data
are for its use in clinically amyopathic DM and specifically anti-MDA5 disease.[188]
[189] However, there are case reports[190]
[191]
[192] and one case series[193] showing favorable outcomes in those with ASyS-ILD. Other therapies that have been
trialed for IIM-ILD include antitumor necrosis factor-α,[194]
[195] tocilizumab,[196]
[197]
[198] and anakinra.[199] More research is required to better evaluate these options for ASyS-ILD.
Antifibrotics
Despite immunosuppression being the primary mode of therapy for ASS-ILD, UIP changes
have been shown to be less responsive to therapy[65] and can represent up to one-quarter of patients with ASyS-ILD[102]; some of whom can develop a progressive fibrotic phenotype. Nintedanib has been
approved for the use in non-IPF (idiopathic pulmonary fibrosis) patients with progressive
fibrosis based on its ability to slow the rate of FVC decline in the INBUILD trial,[200] of which 25% had autoimmune ILD. In IIM-ILD the use of pirfenidone or nintedanib
has been limited with mixed results.[201]
[202] More research is warranted in this area.
PH-Specific Therapies
As mentioned previously, there are several reports linking ASyS with Group 1 PH, although
a substantial proportion of patients develop Group 3 disease. In individuals that
develop Group 3 PH (based on RHC), inhaled treprostinil can be used based on the INCREASE
trial where it was administered to 163 individuals with ILD (25% with CTD-ILD) and
demonstrated improvements in both 6-minute walk distance (6MWD) and brain natriuretic
peptide levels.[203] Patients with PH and minimal ILD may be classified as Group 1 disease after ruling
other possible etiologies and treated accordingly.[204] Given the complexity and challenges with managing such patients, we routinely refer
them to PH specialists. Our threshold for referral is a right ventricular systolic
pressure >30 mm Hg, or any signs of right ventricular dysfunction on echocardiography.
Our Approach to Therapy
The timing of therapy is often dictated by the disease severity, patient's age, comorbidities,
and associated ASyS manifestations. In cases of mild disease, where symptoms are minimal,
and there is no PFT derangement or significant pulmonary parenchymal involvement (<10%)
on CT scans, it may be sufficient to observe patients with close monitoring. However,
in instances where there is a more substantial symptom burden, significant radiographic
involvement or progression, or a decline in PFTs (5% or 10% for FVC and DLCO, respectively),
we have a low threshold for initiating a prednisone taper with a concomitant steroid-sparing
agent ([Fig. 3]).
No clear evidence is available for the superiority of one agent over another. Therefore,
factors such as the prescribing provider's familiarity with different agents, the
patient's underlying comorbidities, drug availability, and the associated side effects
affect the eventual choice. This can be highlighted in our practice of favoring RTX
in patients with concurrent inflammatory arthritis, choosing an alternative to TAC
in patients with renal impairment, or the judicious use of IVIG in patients at risk
of thromboembolism or volume overload. Management of severe and acute exacerbation
of ASyS-ILD is often challenging, requires hospitalization, and may necessitate ICU
level of care. These issues are discussed separately.
While there is no clear evidence for the optimal duration of immunosuppressive therapy,
we aim to limit long-term steroid exposure. We achieve this by overlapping a steroid-sparing
agent with prednisone and ideally decreasing it within 3 months, to a prednisone equivalent
of ≤10 mg/d. We subsequently continue the target dose steroid-sparing agent(s) until
stability is achieved in symptoms, PFTs, and radiographs. We often maintain therapy
for at least 18 to 24 months before consideration of a slow taper of the steroid-sparing
agent accompanied with close monitoring.
We typically use PFTs to monitor disease progression and response to treatment. A
comprehensive PFT (spirometry, lung volumes, and DLCO) is conducted at our initial
encounter with patients and before starting therapy with repeat spirometry and DLCO
assessments every 3 to 4 months, and later every 6 to 12 months once stable. Monitoring
patient-centered outcomes, such as symptoms and quality of life, is crucial for tracking
disease progression and therapy. Additionally, we vigilantly assess therapy-related
adverse events as outlined in [Table 3]. Importantly, we do not routinely rely on imaging to monitor or assess response
to treatment; instead, we employ it when clinically indicated. We incorporate guideline-directed
prophylaxis for osteoporosis and pneumocystis jirovecii pneumonia (PJP), gastroesophageal
reflux (GERD), and aspiration.
Table 3
Drug therapies used in the treatment of antisynthetase-associated ILD
|
Drug
|
Dose
|
Monitoring
|
Adverse effects
|
Comments
|
|
First line
|
|
Corticosteroids
|
0.5–1 mg/kg/d prednisone; methylprednisolone 500–1,000 mg/d for 3 d
|
Annual bone density scan, glucose monitoring
|
Osteoporosis, glaucoma, hyperglycemia, insomnia, weight gain, bruising, mood changes,
myopathy, risk for PJP
|
Disease severity dictates dosing. Taper slowly when steroid-sparing agent has reached
therapeutic effect.
|
|
Second line
|
|
Azathioprine
|
2–3 mg/kg/d (generally not higher than 200 mg/d)
|
TPMT level before initiation; CBC and CMP every 2 wk during dose titration and 4–8
wk thereafter; yearly skin exam
|
Transaminitis, leukopenia, GI intolerance, increased risk of malignancy
|
Start at 50 mg/d and titrate by 50 mg/wk if tolerating. May need dose adjustment based
on TPMT level. Controls myositis effectively.
|
|
Mycophenolate mofetil
|
2,000–3,000 mg/d divided in two doses
|
CBC count and CMP every 2 wk during dose titration and every 4–8 wk thereafter; yearly
skin examination
|
Transaminitis, leukopenia, GI intolerance, increased risk of malignancy, difficulty
concentrating
|
Start at 500 mg twice a day; titrate slowly over a few weeks according to tolerability.
Controls skin disease effectively
|
|
Third line
|
|
Cyclosporin A
|
2–5 mg/kg/d divided in two doses
|
CBC, CMP, CsA trough levels every wk for first month and every 4 wk thereafter; yearly
skin exam and lipid panel
|
Renal toxicity, hypertension, hyperlipidemia, tremors, hyperglycemia, increased risk
of malignancy
|
Start at 2 mg/kg and titrate dose by 0.5 mg/kg Maintain serum trough level 100–200 ng/mL.
Controls myositis and joint disease effectively
|
|
Tacrolimus
|
Typical starting dose is 0.5–1.0 mg or 0.075 mg/kg twice a day
|
CBC count, CMP, TAC trough level every week for the first month and every 4 wk thereafter;
yearly skin exam and lipid panel
|
Renal toxicity, hypertension, hyperlipidemia, tremors, hyperglycemia, increased risk
of malignancy
|
Titrate to a trough of 3–6 ng/mL
Controls myositis and joint disease effectively
|
|
Cyclophosphamide
|
2 mg/kg po daily; 500–750 mg/m2 IV monthly
|
CBC count and CMP every 2 wk initially, UA monthly, lifelong urine cytologic analysis
annually
|
Myelosuppression, malignancy, hemorrhagic cystitis, infertility
|
Maintain WBC >3,500/mm3.
Dose adjust by 25% according to WBC count of initial IV dose; not to exceed 1,000 mg/m2
Often reserved for acute exacerbation
|
|
Adjunct therapy
|
|
Rituximab
|
1,000 mg day 0 and day 14; repeat about every 6 months
|
Hepatitis and latent TB screening; immunoglobulin, CBC prior to infusions; CD19/CD20
levels before initiation and sometimes during therapy
|
Hepatitis reactivation, increased risk of severe SARS-CoV-2 infection, infusion reactions,
progressive multifocal leukoencephalopathy
|
Reserved for severe or resistant disease as an adjunct therapy.
Controls myositis and joint disease effectively
|
|
Human intravenous immunoglobulin
|
2 g/kg/mo divided over 3–5 d
|
Screen for IgA deficiency before initiation
|
VTE, volume overload, headaches (aseptic meningitis), antibody-mediated cytopenias,
anaphylaxis, infusion reactions
|
Initially prescribed for 6 months before slowly tapering by spacing out therapy every
5–8 wk before withdrawal.
Not considered to be immune-suppressive. Reserved for severe and resistant disease
as an adjunct therapy. Can be used in acute exacerbations.
|
Abbreviations: CBC, complete blood count; CMP, comprehensive metabolic panel; CsA,
ciclosporin A; ILD, interstitial lung disease; IgA, immunoglobulin A; IVIG, IV immunoglobulin;
mo, month(s); PJP, Pneumocystis jirovecii pneumonia; TAC, tacrolimus; TB, tuberculosis; TPMT, thiopurine S-methyltransferase;
UA, urinalysis; VTE, venous thromboembolism; WBC, white blood count; wk, week(s).
Severe Disease and Critically Ill Patients
Although the data for IIM-ILD (and specifically ASyS-ILD) developing respiratory failure
are limited, it confers a grim prognosis, with mortality estimates from acute exacerbations
upwards of 40%.[205]
[206]
[207] The acute respiratory failure that develops in these patients resembles acute respiratory
distress syndrome (ARDS) with histological correlates of DAD.[208]
[209] Despite the literature outlining a poor prognosis for patients with CTD-ILD and
acute respiratory failure, we believe that ASyS-ILD presents a unique subset of patients
that may have better outcomes[210] especially if invasive mechanical ventilation support is optimized.[211] This stems from our observation that many of the patients are younger, have otherwise
less co-morbidities, are primarily with single organ (lung) diseases (making them
candidates for other advanced interventions, e.g., lung transplantation), and the
development of acute respiratory failure is likely reversible.
To this end, we actively search for an infectious etiology. We find that deep endotracheal
aspirate or, in patients who can tolerate it, bronchoalveolar lavage has a better
yield to pick up infectious agents in individuals on background immunosuppression.[212]
[213]
[214] Nevertheless, since infection has been documented as a common etiology in acute
respiratory worsening,[215] we often empirically treat patients with broad-spectrum antibiotics that include
azithromycin for its immunomodulating effects in ILD exacerbations[216] and ALI.[217] We do not incorporate procalcitonin levels in our antimicrobial coverage algorithm.
As acute respiratory failure may be the first manifestation of ASyS-ILD, we have a
high index of suspicion in patients with new-onset ILD. In the absence of an active
infection, or other causes of dyspnea, we depend on thorough history and physical
examination. We focus on hand, neck, and back examinations that are often overlooked
in critically ill patients for dermatological or rheumatic features of ASyS that can
provide further insight into the patients' underlying disease activity. This is vital
for patients presenting for the first time with ASyS-ILD in expediting their diagnosis.
We also search for other markers, including creatinine kinase levels, aldolase levels,
and repeat of their antibody serology that may increase above baseline during flares.
We pulse such patients with 1 g of intravenous methylprednisolone for 3 days followed
by prednisone 1 mg/kg/d (max 60 mg). Although CYC has traditionally been used in severe
disease and acute exacerbations for remission, we prefer using IVIG due to its lower
associated toxicity. A steroid-sparing agent (AZA, MMF, or TAC) is also routinely
started based on other ASyS organ involvement. We prefer using TAC based on our anecdotal
experience of better efficacy and faster onset action and data for its use in refractory
disease. In patients who fail to respond within the first 5 to 7 days or present with
fulminant respiratory failure, we typically add a second steroid-sparing agent (CYC,
RTX, and TAC, if not used previously). We rarely use plasmapheresis except in select
cases. Early referral for extracorporeal membrane oxygenation (ECMO) and consideration
of lung transplant evaluation where available are also critical.
Respiratory support is often needed in these patients. We ensure that the patient
and their family are aware of the reserved prognosis of invasive mechanical ventilation
use during respiratory failure[218] and explore their goals of care; we also engage the palliative care team early in
the patient's disease course. We incorporate noninvasive mechanical ventilation use
due to its potential to decrease intubation rates, extrapolated from cohorts of respiratory
failure without ILD.[219] We prefer high-flow nasal cannula due to less concern with risk of large tidal volume
ventilation.[220]
[221] When intubated, patients are maintained with lung-protective ventilation in line
with the ARDS literature.[222] Moreover, patients are kept net-neutral or net-negative fluid balance.[211]
[223] Eligibility or pre-existing enrollment for lung transplantation is explored and
may help in choosing the appropriate care pathways.
ECMO has become an attractive temporizing therapy. Several cases have demonstrated
its successful use in ASyS-ILD.[224]
[225]
[226]
[227]
[228]
[229]
[230]
[231] We consider this modality in patients that fulfil our center's selection criteria,
especially for those awaiting lung transplantation. Additionally, we believe that
the lung healing benefits of ECMO[232]
[233] complement immunosuppression therapy and provides sufficient time for it to take
effect.
Nonpharmacological Treatment
Nonpharmacological Treatment
Supplemental Oxygen
Supplemental oxygen therapy can help patients with ASyS-ILD in symptomatic relief,
improved exercise tolerance, and theoretical risk reduction of developing PH. Hypoxemia
in addition to disruption of the pulmonary vascular beds by fibrosis contributes to
the development PH in patients with ILD.[234] The physiological hypoxic pulmonary vasoconstriction can be somewhat mitigated by
supplemental oxygen.[235]
[236] Studies on supplemental oxygen effect on dyspnea are conflicting. A small retrospective
study in ILD (not limited to CTD-ILD) found that dyspnea improved with supplemental
oxygen,[237] while a larger retrospective review of 3,126 patients demonstrated worsened dyspnea
on exertion.[238] In a systematic review of 1,509 ILD patients, no improvement in dyspnea was observed
although exercise capacity increased with oxygen.[239] A more robust prospective, single-blinded, randomized study found that dyspnea improves
with supplemental oxygen at baseline but not during peak exercise, despite a significant
improvement in exercise endurance.[240] We routinely screen all our ASyS-ILD patients who complain of significant dyspnea,
reduced exercise tolerance, or those with DLCO is below 50% predicted. We prescribe
oxygen if their saturation falls below 88%, either at rest or on exertion.[241]
[242] Nocturnal oxygen is encouraged for all patients with resting hypoxemia.
Pulmonary Rehabilitation and Exercise
Poor exercise capacity is linked with worse survival in patients with ILD.[243] In a Cochrane review of pulmonary rehabilitation,[244] improvements in dyspnea and 6MWD were observed and maintained at 6 to 12 months.
Muscle strength also improves after 6 months of pulmonary rehabilitation with improved
exercise capacity and quality of life. We therefore offer pulmonary rehabilitation
to all our ASyS-ILD patients[245] and emphasize regular exercise.
Immunization and Prophylaxis
We routinely offer patients the pneumococcal, COVID-19, influenza, and respiratory
syncytial virus (in those who qualify) vaccines irrespective of their immunosuppression
regimen. Alongside vitamin D supplementation, we prescribe oral bisphosphonates for
those we anticipate requiring continued prednisone of ≥2.5 mg/day for >3 months if
they have a moderate risk of fracture.[246] PJP occurs more frequently in IIM-ILD patients,[247]
[248] and is associated with a high mortality rate.[249] We typically prescribe prophylaxis in patients receiving prednisone at a dose of
≥15 mg/d for ≥4 weeks, RTX, or any combination of two or more steroid-sparing agents.
CD4 levels <200/mm3 may also aid in the decision of initiating prophylaxis.
GERD is common in ASyS-ILD especially when esophageal dysmotility is present.[250] We emphasize lifestyle and dietary measures, weight loss, elevation of the head
of bed, and avoiding dietary triggers[251] to limit reflux or micro aspirations. We offer proton pump inhibitors therapy when
indicated.
Lung Transplantation
In patients with end-stage ASyS-ILD, lung transplantation may be their only viable
option. In retrospective studies, the survival of transplanted patients with IIM appeared
to be slightly worse in some,[252] while similar in others[253]
[254] when compared with CTD-ILD. In line with international recommendations,[255] we refer our patients for lung transplant evaluation if they are on supplemental
oxygen, DLCO <40%, progression of disease despite treatment, rapid decline in PFTs,
or any evidence of PH.
ILD Prognosis
Patients with ASyS-ILD have variable disease outcome. Generally, most patients respond
to therapy with either improvement or stabilization in their lung functions. A subset
may continue to deteriorate, are refractory to therapy, or recur. In a cohort of 51
patients with anti-EJ antibody-positive ILD,[82] of whom 44 were followed to assess response to immunosuppression, 34 (77%) improved,
and 10 (23%) stabilized. Disease recurrence was seen in 25%. In another cohort of
87 ASA-ILD with positive anti-Ro-52,[256] 56 (64%), 10 (11.5%), and 21 (24.5%) patients improved, stabilized, and worsened,
respectively. The higher rate of nonresponsive disease in this group may be due to
patient selection that was initially based on positive anti-Ro-52 antibodies prior
to testing for ASA; possibly causing preselection of patients with a worse phenotype
in addition to the lack of anti-Jo-1 positive patients. In 202 patients with ASyS,[257] patients with non-Jo-1 serology had a worse 5- and 10-year cumulative survival,
with the main cause of death in all the population being pulmonary fibrosis and PH.
ASyS-ILD typically shows response to therapy in the first 6 to 12 months,[65]
[80]
[258]
[259] unless refractory. Factors that have been demonstrated to show worse outcomes in
patients with ASyS-ILD include the presence of a UIP pattern on HRCT,[50]
[65]
[89]
[95]
[260] non-Jo-1 serology,[50]
[55]
[77]
[257]
[260]
[261] male gender,[76] and older age at diagnosis.[17]
[53] Mortality in patients with ASyS is considered higher than the average[17]
[53]
[55] often due to pulmonary complications.[261]
[262]
Conclusion
ASyS has a high pulmonary disease burden, with ILD being its most prominent and common
manifestation. Although various classification criteria exist, a high index of suspicion
is crucial when assessing patients with ILD. Different ASAs are associated with distinct
clinical features, often presenting with radiographic disease consistent with NSIP
or OP. In most cases, lung biopsy is unnecessary. Various therapeutic options are
available demonstrating relative success in disease control. However, a subset of
patients experiencing clinical deterioration, unresponsiveness, or becoming critically
ill emphasizes the need for future prospective studies focused specifically on ASyS-ILD
management.
