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Abstract

Background:

Interstitial lung disease (ILD) is the main clinical feature of antisynthetase syndrome (ASS). In the absence of randomized controlled trials to guide therapy, treatment strategies are often extrapolated from other diseases, mainly systemic sclerosis (SSc).

Objectives:

Our aim was to evaluate the dynamics of ILD severity following immunosuppressive treatment (IST) in ASS compared to SSc.

Design:

A multicenter retrospective observational study.

Methods:

ASS (n = 22) and SSc (n = 32) subjects with ILD were included in the registries of three medical centers. All patients received ISTs. We analyzed changes in forced vital capacity (FVC) and diffusion capacity for carbon monoxide corrected for hemoglobin (DLCOc) after treatment initiation using linear mixed-effects models. Changes in high-resolution chest CT scans were analyzed by a radiologist blinded to clinical data.

Results:

The median (interquartile range) age was 66 (59–71), 72% were females, and 81% of IST included mycophenolate mofetil (MMF). Baseline demographics, comorbidities, and pulmonary functions were similar between the groups. Among the ASS group, the mixed-effects models showed significant improvements in FVC% (F = 11.3, p < 0.01) and DLCOc% (F = 7.1, p = 0.015) after treatment initiation over time, while in the SSc group, there were no significant changes in FVC% (F = 0.4, p = 0.551) and DLCOc% (F = 0.8, p = 0.384). Changes in FVC% and DLCOc% were higher in the ASS group compared with SSc (p = 0.017 and p < 0.01, respectively), which persisted after adjustment to steroid use and in a sub-analysis of patients with serial pre- and post-IST pulmonary functions. Both groups had improved total CT scores after IST, without changes in other radiologic scores.

Conclusion:

Immunosuppressive treatment, mostly with MMF, was associated with significant improvement of FVC% and DLCOc% in ASS, compared to their stabilization only in SSc. This should encourage future randomized controlled studies of MMF in ASS patients.

Plain language summary

How interstitial lung disease progresses after immunosuppressive treatment in antisynthetase syndrome vs. systemic sclerosis

Antisynthetase syndrome (ASS) is a rare autoimmune disease that affects the muscles, joints and lungs. Systemic sclerosis (SSc) is also a less rare autoimmune disease that causes scarring of the skin and the lungs, for which there is more abundant clinical trial evidence to support treatment. For both diseases, immunosuppressive treatments are required, which are treatments that lower the activity of the body’s immune system. As there are no official treatment guidelines for managing ASS lung disease, doctors often rely on established treatments for SSc lung disease. For this reason, our aim was to assess how lung disease responds to immunosuppressive treatment in ASS compared to SSc. We looked back at data of 54 patients from three medical center. 22 patients had ASS lung disease and 32 patients had SSc lung disease, all treated with immunosuppressive therapy. We found that lung function has significantly improved in the ASS group after treatment. This improvement was greater than that observed in the SSc group. CT scans, which depict the changes in the relevant lung disease, showed improvements in both groups. Additionally, we identified markers that may help predict how patients with ASS will respond to immunosuppressive treatments. In summary, we found major improvements of ASS lung disease compared to SSc after starting immunosuppressive therapy, supporting the need for additional high-quality research that focus on ASS.

Keywords

high resolution CT lung functions mycophenolate mofetil pulmonary fibrosis steroids

Introduction

Antisynthetase syndrome (ASS) is a relatively rare idiopathic inflammatory myopathy (IIM) that typically presents with interstitial lung disease (ILD), arthritis, myositis, and other systemic inflammatory symptoms.¹ It is characterized by autoantibodies against one of the aminoacyl transfer RNA synthetases, including anti-Jo-1, anti-threonyl (anti-PL7), and anti-alanyl (anti-PL12), among others.² The diagnosis of ASS relies on the combination of antibodies and classical signs and symptoms, with different criteria developed over the years.^1,3,4 Compared with other IIMs, ASS has a higher prevalence of ILD, which is often severe and progressive, and the major cause of disease-related morbidity and mortality.⁵ ASS initial presentation could be an incidental radiologic finding in asymptomatic patients, or respiratory complaints that may precede other systemic symptoms.⁶ The common radiologic patterns seen in ASS by high-resolution CT (HRCT) are non-specific interstitial pneumonia (NSIP) and organizing pneumonia (OP), although a mix of the two patterns or usual interstitial pneumonia (UIP) is also reported.⁷

Corticosteroids are the cornerstone of treatment in ASS-related ILD, both as an induction and maintenance therapy.⁸ Steroid-sparing immunosuppressive treatments (IST) are essential for long-term treatment of ASS given the side effects of corticosteroids and the need for long-term treatment due to frequent relapses.^9,10 However, evidence regarding the efficacy of corticosteroids or IST for ASS-related ILD is scarce. A meta-analysis from 2019 that evaluated the efficacy of therapies for IIM-related ILD found no controlled studies and only 553 patients in their included studies combined.⁸ Therefore, the current practice is based on proven treatments with high-quality evidence for other autoimmune-related ILDs, mostly systemic sclerosis (SSc). Cyclophosphamide was previously considered the first-line treatment in SSc-related ILD.¹¹ Following several large prospective studies, mycophenolate mofetil (MMF),¹² tocilizumab,¹³ and rituximab¹⁴ are now considered by many as the first-line therapies for SSc-related ILD,¹⁵ with MMF as the first priority-based on its better safety profile.¹⁶ Azathioprine is sometimes used but is supported by lower-quality evidence.¹⁷

Whether the mentioned IST has similar effects in SSc- and ASS-related ILD is unknown. This question is of high clinical importance to guide clinicians in their practice, and due to the rareness of ASS, it has still not been addressed by prospective controlled studies. In addition, prior studies were mostly single-center and without a direct comparison between the two diseases. Different groups have recommended the use of both HRCT and pulmonary functions for prognostication and surveillance of patients with SSc and ASS-related ILD.¹⁸ Therefore, the aim of our proof-of-concept multicenter observational study was to evaluate changes in pulmonary functions and radiological variables following IST in patients with ASS and SSc. As direct comparisons between patients with ASS and SSc are lacking, our findings could highlight the different treatment responses in ASS patients, emphasizing the need for designated clinical trials.

Methods

We conducted a retrospective multicenter observational study, including adult subjects with ASS or SSc from registries of three ILD specialty centers in Israel. To be included, the following criteria had to be met: (1) a diagnosis of ASS or SSc according to the criteria by Connors et al. (1) and Van den Hoogen et al.,¹⁹ respectively, (2) at least one follow-up visit between 2017 and 2021 with available medical records, (3) being treated with a steroid-sparing IST, and (4) available serial pulmonary function tests (PFTs) before and after treatment as specified below. We excluded patients with an overlap syndrome. Diagnoses were made by a multidisciplinary discussion in accordance with accepted guidelines and based on history, physical examination, serological analysis, and chest HRCT features.²⁰ The multidisciplinary team included pulmonologists specialized in ILD, rheumatologists, a radiologist specialized in chest imaging, and a pathologist when relevant. In cases of an uncertain diagnosis, bronchoalveolar lavage and transbronchial biopsy were performed, with additional MDD thereafter, as described before.^21,22 ASS diagnosis was based on the criteria by Connors et al.,¹ which included the presence of ASS-specific antibody and additional relevant conditions. Prior to inclusion, all ILD diagnoses were verified by a senior pulmonologist specializing in ILD (A.U.) and a rheumatologist (T.E), according to accepted criteria.¹ The study outcomes for analysis were relative yearly change of forced vital capacity as %predicted (FVC%) and of diffusion capacity for carbon monoxide corrected for hemoglobin as %predicted (DLCOc%), and the change in chest HRCT after treatment initiation.

The study is reported according to STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) checklist,²³ as provided in the Supplemental Appendix.

Pulmonary function tests

PFTs were performed in one of the three medical centers and had to include measurements of FVC% and DLCOc% (lung plethysmograph with total lung capacity (TLC) was considered optional). The inclusion criterion for serial PFTs was considered fulfilled if there was at least one PFT within the 4 months before IST treatment initiation, and one within the 18 months after. PFTs performed less than 4 months after IST treatment initiation were not included in order to allow sufficient time for treatment to become effective. PFTs performed more than 4 months after the end of treatment were not included as well. All PFTs were performed by trained technicians who ensured their correct performance, such as forced expiration. PFT results were interpreted according to accepted standards.²⁴

Radiologic analysis

Radiologic analysis was performed for subjects with available HRCT before and after treatment with IST (up to 1 year before and 1 year after). Analysis was performed by a senior chest radiologist specialized in ILD (T.S.), blinded to the clinical data or diagnosis. CT images were acquired using a 128 × 2 × 0.625 mm or 64 × 0.625 mm detector row scanner. Images were reconstructed with a slice of 1.0–2.0 mm with the same increment.

We performed three radiologic analyses. First, a general analysis was performed by the radiologist, including the presence of pulmonary fibrosis, its predominant pattern (NSIP, UIP, or OP), and whether there was an improvement, no change, or worsening in findings between the scans. Second, each HRCT before and after treatment was classified into limited or extensive ILD according to the diagram described by Goh et al.²⁵ In short, limited ILD was defined as the extent of disease < 20% on HRCT, or FVC ⩾70%predicted in cases of intermediate extent, while other cases were defined as extensive. Third, we scored each HRCT using the Scleroderma Lung Study (SLS) I scoring system,²⁶ which was based on a prior report by Kazerooni et al.²⁷ In short, four parenchymal abnormalities (pure ground glass opacity, lung fibrosis, honeycombing, and emphysema) were scored 0–4 based on their extent (0 = absent, 1 = 1%–25%, 2 = 26%–50%, 3 = 51%–75%, 4 > 75%) in three lung zones: upper (apex to aortic arch), middle (aortic arch to inferior pulmonary veins), and lower (inferior pulmonary veins to diaphragm).

Data analysis

Categorical variables are presented as total (percentage) and compared between groups by Chi-square tests. Continuous variables are presented as medians (interquartile range (IQR)) and compared between groups by Mann–Whitney U test. Absolute yearly change of FVC (%predicted) was calculated as: (FVC%_post–FVC%_initial)/(duration between the tests in years). To account for different initial FVC% values between subjects, we analyzed and presented the relative yearly change (percentage) by dividing the absolute yearly change by the initial FVC%. Similar analyses were performed for DLCOc measurements. The longitudinal changes in FVC and DLCOc between and among subjects with ASS and SSc were analyzed using mixed-effect linear models, with time as a continuous variable. The models included a variance-covariance matrix to model the covariance structure among the repeated measures by subject. A similar method was used to evaluate the effect on change in PFTs of steroid use, as its use was significantly different between the ASS and SSc groups, and of different ASS-related variables. Patients with multiple PFTs (⩾2) before treatment (in addition to ⩾ 1 PFTs after) were included in a sub-analysis, and a comparison of their changes in PFTs before and after treatment was analyzed by similar linear mixed-effects models as presented above. CT scores were compared before and after treatment using the Wilcoxon Signed-Rank test. The extent of the radiologic disease (limited or extensive) was compared before and after treatment using the Related Samples McNemar Change Test. Analyses were carried out using SPSS version 28.0, with a two-sided p-value less than 0.05 considered statistically significant.

Results

Across the 3 registries, 26 subjects had ASS-related ILD and 39 had SSc-related ILD. After exclusions (8 without IST and 3 without relevant PFTs), the study cohort included 22 subjects with ASS and 32 with SSc. The overall median (IQR) age was 66 (59, 71), and 72% were females. ISTs included MMF (44 subjects, 81%), azathioprine (AZA, 7 subjects, 13%), and others (2 subjects with rituximab alone, and 1 with methotrexate). Thirty-two (59%) subjects, of them 20 with ASS, also received glucocorticoids (prednisone in all cases). None of the patients were treated with anti-fibrotic drugs. The median (IQR) follow-up time with PFT was 12 months (10–15).

Table 1 presents a comparison of demographic and clinical characteristics between the ASS and SSc groups. Baseline demographic characteristics and comorbidities were similar between the groups. ILD was the first manifestation in more cases of ASS (64% vs 16%, p < 0.01). The ASS group had a pretreatment median (IQR) FVC% of 72 (60, 87), TLC% of 82 (69, 90), and a DLCOc% of 45 (35, 56), with similar pretreatment PFTs recorded in the SSc group. MMF was used in 82% of ASS cases and 81% of SSc cases (p = 0.96). However, prednisone was more often used concurrently in subjects with ASS (91% vs 43%, p < 0.01). Treatment duration of IST during follow-up was similar between the groups (p = 0.78).

Table 1.

Comparison of demographic and clinical variables between patients with antisynthetase syndrome and systemic sclerosis.

Variable	ASS	SSc	p
Variable	n = 22 (%)	n = 32 (%)	p
Age	67 (62, 68)	61 (56, 73)	0.37
Female sex	17 (77)	22 (69)	0.49
Past/current smokers	10 (46)	8 (25)	0.12
Heart failure	3 (14)	3 (9)	0.62
Interstitial lung disease onset^a			<0.001
Before systemic symptoms	14 (64)	5 (16)
Concurrent	8 (36)	11 (34)
After systemic symptoms	0	16 (50)
Prednisone treatment	20 (91)	12 (43)	<0.01
Prednisone dose (mg/day)	30 (20,40)	20 (20,25)	0.12
MMF treatment	18 (82)	26 (81)	0.96
MMF dose (g/day)	2 (2, 2)	2 (2, 3)	0.37
Treatment duration in follow-up, months	12 (9,17)	13 (11,16)	0.78
Pulmonary functions^b
FEV1, % pred.	74 (61, 86)	72 (68, 88)	0.65
FVC, % pred.	72 (60, 87)	73 (67, 81)	0.72
FEV1/FVC	83 (77, 88)	80 (76,83)	0.18
TLC, % pred.	82 (69, 90)	84 (70, 95)	0.86
DLCOc, % pred.	45 (35, 56)	47 (40, 57)	0.60

Onset of interstitial lung disease is divided into more than 6 months before other systemic symptoms, under 6 months before or after the appearance of systemic symptoms, and after more than 6 months from systemic symptoms.

Pulmonary functions adjacent to initiating immunosuppressive treatment. Of note, 4 patients had missing relevant TLC measurements (3 with SSc and 1 with ASS).

ASS, antisynthetase syndrome; DLCOc, diffusing capacity of the lung for carbon monoxide corrected for hemoglobin; FEV1, forced expiratory volume in the first second; FVC, forced vital capacity; SSc, systemic sclerosis; TLC, total lung capacity.

Changes in PFT after treatment

Among the ASS group, the mixed-effects models found a significant improvement in FVC% (F = 11.3, p < 0.01) and DLCOc% (F = 7.1, p = 0.015) after treatment initiation over time, while in the SSc group, there were no significant changes in FVC% (F = 0.4, p = 0.551) and DLCOc% (F = 0.8, p = 0.384). Figure 1 presents the relative yearly change in FVC% (Panel a) and DLCOc% (Panel b) after treatment, according to the ILD group. The median (IQR) relative FVC% yearly change was 8.1% (1.3, 15.8) in the ASS group and 0.45% (−3, 4.3) in the SSc group, and was statistically different between these two groups (p = 0.017). The median relative DLCOc% yearly change was 8.2% (−3, 12.8) in the ASS group and −2.4% (−8.4,6.1) in the SSc group (p < 0.01). Figure 2 presents the predicted linear model for post-treatment change in FVC% (Panel a) and DLCOc% (Panel b) based on the mixed-effects analyses.

Figure 1.

Relative yearly change (in percentage points) of FVC% (a) and DLCOc% (b) after treatment initiation between subjects with antisynthetase syndrome and systemic sclerosis. Each bar represents a different patient, with a dark-gray color signifying worsening and light-gray—improvement.

Figure 2.

Predicted linear model based on mixed-effect models of FVC% (a) and DLCOc% (b) change over time between subjects with antisynthetase syndrome and systemic sclerosis after treatment initiation.

We compared changes in PFT between subjects with and without prednisone treatment using the linear mixed-effects models. Changes in FVC% over time were not significantly affected by prednisone use (p = 0.393), while there was a trend toward difference in changes of DLCOc% based on prednisone treatment (p = 0.067). Sub-analysis of subjects with SSc also did not show an association between steroid use and different changes in FVC% (p = 0.633) or DLCOc% (p = 0.632).

Subjects with multiple PFTs before and after treatment

Multiple PFTs (i.e., ⩾2 before and ⩾1 after treatment) were available for 13 subjects with ASS and 22 with SSc. Changes in PFTs before and after treatment in the ASS and SSc groups appear in Figure 3. Among the ASS group, the median relative yearly change in FVC% was −1.5% and 5.7%, and in DLCOc% it was −7.6% and 2.3% before and after treatment, respectively. Among the SSc group, the median relative yearly change in FVC% was −3.7% and −0.1%, and in DLCO% it was −6.8% and −2.9% before and after treatment, respectively. Based on the mixed-effects linear models, changes in FVC %predicted over time before treatment were similar between the ASS and SSc groups (p = 0.606), while after treatment there was a trend toward a better response in the ASS compared to the SSc group (p = 0.047). Likewise, the changes in DLCOc %predicted over time before treatment were similar between groups (p = 0.332), with a mild trend for a greater change in the ASS group after treatment (p = 0.142).

Figure 3.

Changes in FVC% (left) and DLCOc% (right) before and after treatment initiation in subjects with antisynthetase syndrome (a, b) and systemic sclerosis (c, d)—per subject (solid lines) and by linear models (dotted line).

Change in HRCT after treatment

Thirty-six subjects (15 ASS, 21 SSc) had serial chest HRCT scans in the year before and after treatment with IST. Improvement after treatment based on the general impression of the radiologist occurred in 9 patients with ASS (60%) and 9 patients with SSc (43%, p = 0.31 for the difference between the groups, Table 2). The median (IQR) total CT scores before treatment were 5 (3, 6) in the ASS group and 5 (4, 7) in SSc. After treatment, the total CT score improved in both the ASS (3 (2, 4), p < 0.01) and the SSc (4 (3, 5), p = 0.03, Table 2) groups. When comparing the change in the total CT score before and after treatment between groups there was a numerically higher improvement in the ASS group (difference of 2 vs 1 point, p = 0.21). Fibrosis scores improved only among the ASS group (p < 0.01). Extensive ILD before treatment was found in 67% of subjects with ASS and 76% of subjects with SSc. After treatment, 40% of ASS and 62% of SSc remained extensive, with non-significant changes in this parameter (Table 2).

Table 2.

Analysis of chest high-resolution CT scans pre- and post-treatment with steroid-sparing agents.

Variable	ASS, n = 15			SSc, n = 21			p1^a	p2^a
Variable	pre	post	p	pre	post	p	p1^a	p2^a
General improvement^b—n (%)	—	9 (60)	—	—	9 (43)	—	—	0.31
Extensive ILD^c—n (%)	10 (67)	6 (40)	0.13	16 (76)	13 (62)	0.25	0.53	0.19
Median (IQR) CT scores:
GGO score^d	2 (0, 3)	1 (0, 1)	0.01	2 (1, 4)	1 (1, 2)	<0.01	0.32	0.25
Honeycombing score^d	0 (0, 1)	1 (0, 1)	0.85	1 (0, 1)	1 (0, 1)	0.16	0.08	0.07
Fibrosis score^d	3 (2, 4)	2 (1, 2)	<0.01	3 (2, 4)	2 (2, 3)	0.19	0.49	0.27
Total CT score^d	5 (3, 6)	3 (2, 4)	<0.01	5 (4, 7)	4 (3, 5)	0.03	0.28	0.04

The p1-value stand for the difference in the pretreatment values between the ASS and SSc groups, while the p2-value stand for the difference in the post-treatment values between the groups.

As estimated by the general impression of the radiologist.

Extensive ILD was defined as involving above 20% of the lungs on chest high-resolution CT.

Calculated based on the extent of the feature in HRCT with scores of 0–4 summed in three areas.

ASS, antisynthetase syndrome; GGO, ground glass opacities; ILD, interstitial lung disease; SSc, systemic sclerosis.

Antisynthetase syndrome sub-analysis

Table 3 presents an in-depth analysis of subjects with ASS. ASS-related antibodies included Jo-1 (n = 10, 45%), PL-7 (n = 6, 27%), PL-12 (n = 4, 18%), and EJ (n = 2, 9%). Of note, SSc-related antibodies included ANA (n = 28, 80%), anti-topoisomerase I (n = 21, 60%), anti-RNA polymerase III (n = 5, 14%), and anti-centromere (n = 4, 11%). Radiologic patterns in HRCT were NSIP (n = 14, 64%), OP (n = 7, 32%), and UIP in one patient. In an exploratory subgroup analysis, we assessed associations between changes in PFT after treatment and serological or radiologic variables using mixed-effect models. Linear models for the significant associations appear in Figure S1. The positive change in FVC% over time was greater in subjects with anti-Jo-1 (p = 0.02, Figure S1(A)) and with OP radiologic pattern (p = 0.03, Figure S1(B)). The positive change in DLCOc% over time was higher in subjects with anti-Ro-52 (p = 0.01, Figure S1(C)).

Table 3.

Disease-related characteristics of patients with antisynthetase syndrome.

Pt #	Age y/sex	ASS Ab.	Other selected Ab	Systemic symptoms	Steroid-sparing	HRCT pattern	HRCT improved^a
1	75/F	EJ	Ro52	Mechanic hands	MMF	NSIP	Yes
2	67/M	Jo-1	—	Myositis, Polyarthritis	MMF	UIP	No
3	68/F	Jo-1	Ro52	Mechanic hands, Polyarthritis	MMF	NSIP	Yes
4	65/F	PL-12	Ro52	Polyarthritis	MMF	NSIP	Yes
5	68/F	PL-7	—	—	MMF	NSIP	—
6	62/F	PL-12	—	Myositis	MMF	OP	Yes
7	70/F	Jo-1	Ro52	Myositis, Polyarthritis	MMF	NSIP	—
8	67/F	PL-7	KU	Raynaud	MMF	NSIP	—
9	39/M	PL-7	Ro52	Polyarthritis	MMF	NSIP	—
10	78/M	PL-7	—	—	MMF	OP	No
11	44/F	Jo-1	—	Myositis	MMF	NSIP	No
12	62/F	Jo-1	Ro52, Ro60, KU	Mechanic hands, Raynaud	MMF	OP	No
13	80/F	Jo-1	—	Polyarthritis, myositis	AZA	NSIP	—
14	67/F	PL-7	—	—	AZA	OP	—
15	82/M	Jo-1	—	Myositis	AZA	NSIP	—
16	53/F	EJ	Ro52	Polyarthritis	MMF	OP	Yes
17	65/F	PL-7	Ro52	—	MMF	NSIP	Yes
18	66/F	PL-12	—	Polyarthritis	MMF	NSIP	No
19	64/F	PL-12	—	—	MMF	NSIP	Yes
20	60/F	Jo-1	Ro52	Mechanic hands, Polyarthritis	MMF,R	OP	Yes
21	64/F	Jo-1	Ro52	Myositis	AZA, R	NSIP	No
22	68/M	Jo-1	Ro52	Mechanic hands, polyarthritis	MMF	OP	Yes

Assessed only for patients with available high-resolution chest CT scans before and after treatment (up to 1 year before and 1 year after).

Ab, antibodies; ASS, antisynthetase syndrome; AZA, azathioprine; DLCOc, diffusing capacity of the lung for carbon monoxide corrected for hemoglobin; FVC, forced vital capacity; MMF, mycophenolate mofetil; NSIP, nonspecific interstitial pneumonia; OP, organizing pneumonia; R, rituximab; UIP, usual interstitial pneumonia.

Discussion

In this proof-of-concept study, we evaluate the dynamics of ILD-related parameters, including PFTs and HRCT features, in subjects with ASS and SSc treated with IST. Subjects with ASS had an increase in FVC% and DLCOc% after IST treatment, while these remained stable among subjects with SSc. These changes over time were significantly different between the ASS and SSc groups, having larger improvements in the ASS group. A sub-analysis of patients with multiple PFTs before and after treatment showed similar trends—subjects with ASS demonstrated clear improvement in PFT, while the benefit in subjects with SSc was in the form of stabilization and preservation of PFT. Among subjects with ASS, positive anti-Jo-1 and OP radiologic patterns were associated with a greater improvement in FVC%, while positive anti-Ro-52 was associated with DLCOc% improvement. Finally, our radiological analyses showed improvements in the total CT scores of both groups, while there was only a trend toward improvement in the other CT parameters.

The American College of Rheumatology recently issued a summary of their yet-to-be-published guidelines for the treatment of ILD in patients with systemic autoimmune rheumatic diseases, including IIM and SSc.¹⁵ As first-line IST, they recommend using MMF for SSc, and MMF, AZA, rituximab, or cyclophosphamide, together with glucocorticoids for IIM. However, the British Society for Rheumatology guidelines on the management of IIM from 2022 state that an additional non-steroidal treatment should only be considered, and as a weak recommendation with low-quality evidence.¹⁰ A recent review by Hallowell and Danoff presented a treatment scheme for myositis-associated ILD with concurrent initiation of IST with prednisone, preferably MMF or AZA.²⁸ Our findings support the early initiation of IST in patients with ASS-related ILD, given the improvement in PFTs and the stabilization or improvement of radiologic features. This is also reinforced by the improved variables compared to patients with SSc-related ILD, in which MMF is already considered a first-line therapy.¹⁶ We chose SSc for comparison because of the high-quality evidence for SSc-ILD, compared with any other connective-tissue-disease-related ILD (CTD-ILD). A comparison between ASS- and SSc-related ILDs is rather novel. The RECITAL randomized controlled trial in patients with SSc- and IIM-related ILD found that rituximab was not superior to cyclophosphamide, although they have yet to report on the comparison of the effect between the groups.¹⁴ A retrospective cohort by Fischer et al. included 125 subjects with CTD-ILD, including SSc and polymyositis/dermatomyositis that were treated with MMF. This study did not find a difference in the improvement of PFT between diagnoses.²⁹

Our reported changes in PFTs after IST initiation were generally in line with prior research. Swirgis et al. described changes in PFT before and after treatment with MMF in 28 patients with a CTD-ILD diagnosis during approximately 1 year and found an overall 2.3% improvement in FVC and 2.6% in DLCOc.³⁰ In one of the largest observational cohorts among 110 patients with IIM-related ILD, treatment with MMF or AZA was also associated with significant improvements in FVC and DLCOc, although the increase in DLCOc was largely limited to patients treated with AZA.³¹ The minimal clinically important difference in FVC% among SSc patients was assessed by Kafaja et al. using data from the Scleroderma Lung Study I and II.³² The authors found that a 3.0% to 5.3% yearly increase in FVC was the cutoff for improvement, while a −3.0% to −3.3% yearly change was the cutoff for worsening. Although our findings could not indicate causality, the fact that changes in FVC% among the ASS group were higher than the mentioned cutoff show promise. The minimal clinically important differences in FVC% and DLCO% specifically in subjects with ASS are important and should be the aim of future larger prospective studies.

Variables that are associated with improved response to therapy are of interest for better patient selection and personalization of IST among those available. The current literature in this field for subjects with ASS is scarce and conflicting. A cohort of 828 subjects with ASS did not show a difference in overall mortality based on the ASS-related antibody.³³ On the contrary, and in line with our findings, Sreevilasan et al. found better survival in anti-Jo-1 positive ASS patients after treatment.³⁴ While we found a higher change in DLCOc in subjects with anti-Ro-52, this antibody is known to be associated with more severe disease and lower response to treatment,³⁵ although these associations were shown to vary based on the IST.³⁶ Of note, other factors could contribute to the treatment effect and survival, such as patients’ racial differences and geographic location. For example, a large international study of over 9000 patients with SSc found significant differences in disease presentation and prognosis between different races, independent of other confounders.³⁷

Improvement in radiologic features was less pronounced than those seen with PFTs, although almost all still improved in the ASS group. A low correlation between PFT and radiologic features was found by Zamora at el., which reported on the outcomes of 90 ASS patients. In their study, while PFTs were stable (−0.3% FVC yearly change), 53% had worsened ILD.³⁸ HRCT is one of the main tools for monitoring ILD in general, specifically in ASS and SSc patients.^9,18,39 However, it might be a less sensitive tool, especially with semi-quantitative methods, as done in our study. Occhipinti at el. examined the value of quantitative CT analysis as a prognostic tool in ASS and showed that while specific changes in HRCT pattern did not correlate with functional parameters, the quantitative total lung volume did Occhipinti et al.,⁴⁰ showing promise for future research. Still, in the SLS II trial, the quantitative radiological analysis at 24 months in patients with SSc-related ILD who were treated with either MMF or cyclophosphamide showed that neither the whole-lung ILD amount nor the whole-lung fibrosis amount changed following treatments, compared to the improvements in pulmonary functions.¹² Other factors that might explain the less significant changes in radiological variables are the relatively short follow-up period and limited sample size.

Our study has limitations. First, the study findings could not indicate causality given its retrospective design, limited follow-up period, and lack of a non-IST-treated control group. Therefore, factors such as natural disease fluctuations, selection bias, and others should be considered when interpreting our results. Second, the limited sample size may not be representative, reducing the statistical power of the study. The radiological assessment by a single radiologist could also impact the generalizability of the results. Third, we could not fully adjust for the effect of treatment with prednisone, which was more prevalent in the ASS group, and we were not able to account for the different prednisone doses. Fourth, the study was designed to examine differences between ASS and SSc, and as IST treatment was similar between the groups, analysis of related adverse events was beyond our scope. The overall disease duration was also beyond the study scope, as many patients had known ILD before initiating follow-up in one of the included medical centers. Fifth, selection and referral biases are possible by excluding patients without serial PFTs and the inclusion of patients from ILD specialty centers only. Sixth, the 12-month follow-up period might not be sufficient to assess long-term efficacy and disease progression. Finally, although we used linear mixed-effects models to account for variability in PFT timing between patients, that may still have an effect on our results.

Conclusion

Our proof-of-concept study demonstrated more pronounced improvements in FVC% and DLCOc% following IST initiation, mostly with MMF, in subjects with ASS compared to those with SSc. These positive results remained similar after adjusting for steroid therapy and in sub-analyses. We also found specific ASS-related serological and radiologic variables that correlate with PFT improvement after IST initiation. The unique features of ASS should encourage future prospective controlled studies designed for this patient population to support clinical practice guidelines.

Supplemental Material

sj-docx-1-tar-10.1177_17534666251336896 – Supplemental material for Dynamics of interstitial lung disease following immunosuppressive treatment differ between antisynthetase syndrome and systemic sclerosis

Supplemental material, sj-docx-1-tar-10.1177_17534666251336896 for Dynamics of interstitial lung disease following immunosuppressive treatment differ between antisynthetase syndrome and systemic sclerosis by Ophir Freund, Tali Eviatar, Roni Meidan, Tamar Shalmon, Dana Stav, Tzlil Hershko, Tal Moshe Perluk, Ori Wand, Sonia Schneer, Yochai Adir, David Shitrit, Ori Elkayam, Amir Bar-Shai and Avraham Unterman in Therapeutic Advances in Respiratory Disease

Footnotes

Acknowledgements

None.

Declarations

ORCID iDs

Ophir Freund

Avraham Unterman

Supplemental material

Supplemental material for this article is available online.

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