Abstract
Objective
Interstitial lung disease (ILD) is a leading cause of mortality in SSc. Little is known about the benefits of immunosuppressive drugs in mild ILD. Our aim was to determine whether use of CYC or MMF was associated with an improved ILD course in patients with normal or mildly impaired lung function.
Methods
A retrospective cohort of SSc subjects with ILD, disease duration below seven years and no exposure to CYC or MMF prior to the baseline visit was constructed from the Canadian Scleroderma Research Group registry. Subjects were categorized as having mild ILD if baseline forced vital capacity (FVC % predicted) was >85%. The primary exposure was any use of CYC or MMF at the baseline visit. FVC at one year was compared between exposed and unexposed subjects, using multivariate linear regression.
Results
Out of 294 eligible SSc-ILD subjects, 116 met criteria for mild ILD. In this subgroup, mean (s.d.) disease duration was 3.7 (2.0) years. Thirteen (11.2%) subjects were exposed to CYC or MMF at baseline. The one-year FVC was higher in exposed subjects compared with unexposed subjects, by a difference of 8.49% (95% CI: 0.01–16.98%). None of the exposed subjects experienced clinically meaningful progression over two years, whereas 24.6% of unexposed subjects did.
Conclusion
In this real-world setting, CYC/MMF exposure at baseline was associated with higher FVC values and a lower risk of progression among subjects with mild ILD. These data suggest a window of opportunity to preserve lung function in SSc-ILD.
Keywords: scleroderma and related disorders, respiratory, epidemiology, immunosuppressants, DMARDs
Rheumatology key messages
Systemic sclerosis-associated interstitial lung disease with normal or mildly impaired lung function is frequent.
Immunosuppressive drugs were associated with better lung function at one year in this population.
A window of treatment opportunity may exist in systemic sclerosis-associated interstitial lung disease.
Introduction
Interstitial lung disease (ILD) is a common complication of SSc, affecting up to 50% of patients [1]. ILD is associated with significant morbidity and, along with pulmonary arterial hypertension, is the leading cause of premature mortality in SSc [2]. SSc-ILD is currently treated with immunosuppressive drugs, namely CYC and MMF, with randomized controlled trials supporting their use in patients with moderately severe, active ILD [3–5]. In fact, whereas progressive deterioration in lung function was observed in the absence of therapy [6], immunosuppressive drugs generally halted this progression in treated patients.
However, these drugs are generally ineffective in improving lung function meaningfully. This lack of improvement suggests that the loss of pulmonary function resulting from established lung fibrosis reflects irreversible lung damage. Some authors have suggested that earlier intervention, when lung function is still relatively normal or only mildly impaired, could represent an opportunity for preventing progressive lung disease and functional compromise [7, 8]. However, little is currently known about the benefits of immunosuppressive drugs in patients with mild SSc-ILD, as they were mostly excluded from randomized controlled trials [3, 5].
The primary objective of this study was therefore to determine whether use of immunosuppressive drugs was associated with improved lung function in SSc patients with mild ILD. A secondary objective was to determine whether this association differed between SSc patients with mild ILD vs those with more severe lung functional impairment. Finally, we aimed to explore potential predictors of disease progression in untreated patients with mild SSc-ILD.
We hypothesized that immunosuppression was effective in mild ILD, as this stage of ILD may represent a more active and inflammatory phase of disease with potential for reversibility. We also hypothesized that effectiveness of drugs was at least comparable, if not superior, among those with mild ILD compared with those with lower baseline lung function.
Methods
A retrospective cohort of SSc-ILD subjects within seven years of disease onset and no prior CYC/MMF exposure was constructed from the Canadian Scleroderma Research Group (CSRG) registry. Forced vital capacity (FVC, % predicted) at one year was compared according to exposure to CYC/MMF, using a multivariate linear regression model.
Sources of data
We studied patients enrolled in the CSRG registry with a baseline visit between August 2004 and July 2017. Briefly, subjects are recruited from 14 sites across Canada and from one site in Mexico and must have a diagnosis of SSc verified by an experienced rheumatologist, be over 18 years of age and be fluent in English, French or Spanish. Over 98% of the cohort meets the 2013 ACR/EULAR classification criteria for SSc [9]. All subjects recruited in the registry are assessed yearly by standardized clinical exams, self-reported questionnaires and lab investigations.
Study population
We identified SSc patients with ILD, disease duration below 7 years since the first non-Raynaud manifestation and no exposure to CYC or MMF prior to the baseline visit. The presence of ILD was determined using a published clinical decision rule [1]. This algorithm considered ILD to be present if a high-resolution computed tomography (HRCT) scan of the lung was interpreted by an experienced radiologist as showing ILD or, in the case where no HRCT was available, if either a chest X-ray was reported as showing increased interstitial markings (not thought to be due to congestive heart failure) or fibrosis, and/or if a study physician reported the presence of typical ‘velcro-like crackles’ on physical examination. Patients were then categorized as having mild, moderate or severe ILD if the FVC at baseline was >85%, 45–85% and <45% of predicted value, respectively [3, 5].
In our study, the time of cohort entry (or ‘baseline’ visit) corresponded to the actual first CSRG visit for patients with prevalent ILD, whereas for patients with incident ILD, the baseline visit corresponded to the follow-up visit when ILD was first recorded in the database. Included subjects were observed from study baseline until outcome assessment, or until censoring due to death, loss of follow-up or last study visit, whichever occurred first. Ethics committee approval for this study was obtained at the Jewish General Hospital (Montreal, Canada) and at all participating CSRG study sites.
Exposure definition
The primary exposure was any use of CYC or MMF at the baseline visit. These two drugs were combined under a single exposure category, given that a randomized trial demonstrated their equivalent efficacy in SSc-ILD [5]. An ‘intention-to-treat’, time-invariant exposure definition was used, i.e. subjects were categorized as exposed or unexposed based on their exposure status at the baseline visit.
Outcome measures
The primary outcome was FVC % predicted at the one-year follow-up visit. Secondary outcomes included FVC % predicted at two years, diffusion capacity of the lungs for carbon monoxide (DLCO) % predicted at one and two years, clinically meaningful progression at one and two years, as well as time to clinically meaningful progression (defined as ⩾10% relative decline in % predicted FVC from baseline, or ⩾5% to <10% relative decline in % predicted FVC with ⩾15% relative decline in % predicted DLCO) [10, 11].
Other covariates
The description and definition of other covariates are detailed in the Supplementary Material, section Description of Other Covariates, available at Rheumatology online.
Statistical analysis
Baseline characteristics
Descriptive statistics were used to summarize the baseline characteristics of the study cohort, stratified by disease severity and by exposure to CYC/MMF at baseline. Continuous data were reported as means with standard deviations and categorical data were presented as percentages. Group comparisons were performed using two-sample t-tests (assuming unequal variances).
Primary analyses
First, to determine whether use of immunosuppressive drugs was associated with improved lung function in mild SSc-ILD, we used a multivariate linear regression model to compare FVC at one year between exposed and unexposed subjects within the mild ILD subgroup. The model was adjusted for disease duration, FVC, DLCO, modified Rodnan skin score (mRSS) and shortness of breath at baseline (as continuous covariates). The model also included an interaction between CYC/MMF exposure and baseline FVC (as a continuous covariate) to account for the possibility that baseline FVC modified the CYC/MMF effect even within the mild ILD subgroup. FVC at baseline was centred to the mean to reduce its correlation with the interaction term.
Then, to determine whether this association differed between SSc patients with mild ILD vs those with more severe lung functional impairment, we repeated the analysis within the moderate ILD subgroup for comparative purposes.
Sensitivity analyses
We conducted multiple sensitivity analyses to assess the robustness of our findings. First, to minimize survival bias, we repeated the primary analyses using a study population comprised of subjects with SSc disease duration of less than three years. Second, we repeated the analyses restricted to subjects with a diagnosis of ILD confirmed by HRCT. Third, to account for potential residual confounding from omitted variables, we extended the multivariate analyses to additionally adjust for age, sex, race, smoking history (ever) and anti-topoisomerase I antibodies (extended model 1); plus the presence of arthritis, myositis and gastroesophageal reflux disease (extended model 2); plus corticosteroid use (extended model 3); or for presence of any ground-glass opacities, fibrotic interstitial changes, honeycombing and traction bronchiectasis (extended model 4). Fourth, we repeated the primary analyses using multiple imputation to account for missing values (see Supplementary Material, section Multiple Imputation, available at Rheumatology online) [12]. Fifth, to address potential misclassification of immunosuppressive drug exposure in patients exposed to AZA or MTX, we repeated the analyses with exposure being defined as any use of CYC, MMF, AZA and/or MTX, while excluding patients with previous exposure to any of these drugs prior to baseline. Finally, to account for improper modelling of lung disease severity when FVC is dichotomized at a cut-off of 85%, we repeated the analyses using alternative FVC cut-offs (100%, 90%, 80% and 70%). We also repeated the analyses using data from the entire SSc-ILD cohort and used the interaction term between exposure to CYC/MMF and baseline FVC to assess the modifying effect of higher vs lower baseline FVC when modelled as a continuous covariate.
Secondary exploratory analyses
Secondary analyses were performed to assess the association between CYC/MMF exposure and the above-mentioned secondary outcomes, using multivariate linear regression for continuous outcomes and multivariate logistic regression for categorical outcomes. All models were adjusted for disease duration, FVC, DLCO, mRSS and shortness of breath at baseline, and included an interaction between CYC/MMF exposure and baseline FVC. Descriptive statistics were also used to summarize the pulmonary function trajectories and occurrence of progression and death over two years, stratified by disease severity and by exposure to CYC/MMF at baseline. Finally, for time-to-event outcomes, we performed unadjusted Kaplan-Meier survival analyses by baseline exposure.
We also explored potential predictors of clinically meaningful progression among untreated patients with mild SSc-ILD, using descriptive statistics to summarize their baseline characteristics according to the occurrence of progression at two years. Group comparisons were performed using two-sample t-tests (assuming unequal variances).
All statistical analyses were performed with R version 3.3.1.
Results
Baseline characteristics of the study cohort
Out of 294 SSc-ILD subjects meeting inclusion criteria, 116 (47%), 130 (52%) and 3 (1.2%) had mild, moderate and severe ILD, respectively (Fig. 1). ILD was diagnosed by HRCT when available (82%), otherwise by chest X-ray (4.8%), typical ‘Velcro-like crackles’ (11%) or chest X-ray with ‘Velcro-like crackles’ (2.7%). Exposure to CYC and MMF were recorded at baseline in 28 (9.5%) and 14 (4.8%) subjects, respectively. None of the study subjects were exposed to rituximab or tocilizumab. Subjects were followed for a mean (s.d.) of 3.6 (3.2) years. Follow-up visits were available in 235 (80%) subjects at one year and in 199 (68%) subjects at two years. Over these two years, 35 (12%) deaths were reported overall, including 23 SSc-related deaths, five non-SSc-related deaths and seven deaths of unknown cause. Among all deaths, 11 (32%) were attributed to SSc-ILD.
Fig. 1.
Flowchart of study population with SSc-ILD and no prior exposure to CYC/MMF
Table 1 presents the baseline characteristics of the cohort, stratified by disease severity and exposure to CYC/MMF. In mild ILD, exposed subjects were more likely to have arthritis, to be negative for anti-centromere autoantibodies, to have ground-glass opacities on HRCT and to be exposed to gastroprotective agents compared with unexposed subjects.
Table 1.
Baseline characteristics of whole cohort, stratified by lung disease severity and by exposure to CYC/MMF
| Mild ILD (n = 116) | Moderate ILD (n = 130) | |||
|---|---|---|---|---|
| Unexposed (n = 103) | Exposed (n = 13) | Unexposed (n = 106) | Exposed (n = 24) | |
| Demographics | ||||
| Age, years | 56.6 (11.9) | 53.4 (11.2) | 54.8 (12.6) | 51.6 (11.6) |
| Female | 81 (79%) | 11 (85%) | 78 (74%) | 19 (79%) |
| White | 76 (75%) | 9 (75%) | 81 (79%) | 14 (61%) |
| Smoking, ever | 59 (59%) | 7 (58%) | 64 (62%) | 10 (42%) |
| SSc clinical characteristics | ||||
| Disease duration, years | 3.8 (2.1) | 3.0 (1.5) | 2.8 (1.9) | 2.6 (1.5) |
| Diffuse subtype | 53 (51%) | 9 (69%) | 61 (58%) | 14 (58%) |
| mRSS (0–51) | 12.3 (11.4) | 13.8 (10.2) | 15.2 (11.9) | 15.3 (10.4) |
| Arthritis | 26 (26%) | 8 (62%)a | 23 (23%) | 9 (38%) |
| Inflammatory myositis | 8 (8%) | 2 (15%) | 20 (19%) | 5 (21%) |
| GERD | 53 (58%) | 9 (82%) | 63 (64%) | 12 (55%) |
| Pulmonary hypertension | 11 (16%) | 1 (8%) | 18 (23%) | 3 (18%) |
| Disease activity (0–10) | 2.7 (2.7) | 3.7 (2.0) | 4.4 (2.7) | 5.7 (2.6)a |
| Disease severity (0–10) | 3.2 (2.3) | 4.2 (2.1) | 4.9 (2.5) | 5.2 (2.3) |
| Disease damage (0–10) | 3.5 (2.3) | 4.5 (2.0) | 4.8 (2.4) | 5.9 (2.0)a |
| ILD characteristics | ||||
| FVC, % predicted | 99.7 (10.2) | 97.1 (12.2) | 71.2 (10.1) | 62.8 (11.0)a |
| TLC, % predicted | 99.4 (11.7) | 97.7 (14.6) | 75.3 (11.3) | 65.8 (13.4)a |
| DLCO, % predicted | 71.8 (23.0) | 66.1 (15.6) | 52.9 (16.5) | 44.8 (14.4) |
| Shortness of breath (0–10) | 1.6 (2.3) | 3.0 (3.1) | 3.1 (2.8) | 4.0 (2.9) |
| HRCT: | ||||
| Ground glass, any | 32/53 (60%) | 8/9 (89%)a | 26/48 (54%) | 14/16 (88%)a |
| Ground glass, moderate-severe | 4/53 (8%) | 0/9 (0%)a | 5/48 (10%) | 2/16 (13%) |
| Fibrotic interstitial changes, any | 37/56 (66%) | 6/8 (75%) | 39/53 (74%) | 16/17 (94%)a |
| Fibrotic interstitial changes, moderate-severe | 3/56 (5%) | 1/8 (13%) | 7/53 (13%) | 3/17 (18%) |
| Honeycombing, any | 5/53 (9%) | 1/7 (14%) | 13/48 (27%) | 5/15 (33%) |
| Honeycombing, moderate-severe | 0/53 (0%) | 0/7 (0%) | 5/48 (10%) | 2/15 (13%) |
| Traction bronchiectasis, any | 9/56 (16%) | 2/8 (25%) | 17/52 (33%) | 9/16 (56%) |
| Serologies | ||||
| Anti-centromere | 22 (26%) | 0 (0%)a | 15 (17%) | 1 (5%) |
| Anti-topoisomerase 1 | 18 (21%) | 1 (20%) | 27 (31%) | 15 (71%)a |
| Anti-RNA polymerase III | 20 (23%) | 3 (60%) | 21 (24%) | 1 (5%)a |
| Anti-Ro52/TRIM21 | 26 (30%) | 1 (20%) | 30 (34%) | 9 (43%) |
| Other medications | ||||
| Corticosteroids (any dose) | 11 (11%) | 5 (38%) | 29 (27%) | 12 (50%) |
| Gastroprotective agents | 72 (70%) | 12 (92%)a | 76 (72%) | 16 (67%) |
Data are presented as mean (s.d.) for continuous variables and as frequency (%) for categorical variables.
In mild ILD, exposed subjects were significantly more likely to have arthritis, to be negative for anti-centromere antibodies, to have any ground-glass opacities on HRCT and to be exposed to gastroprotective agents compared with unexposed subjects. In moderate ILD, exposed subjects had significantly higher disease activity and damage scores and lower FVC and TLC % predicted values compared with unexposed subjects. They were also more likely to be positive for anti-topoisomerase I antibodies and negative for anti-RNA polymerase III antibodies, and to have ground-glass opacities and fibrotic interstitial changes on HRCT.
DLCO: diffusion capacity of the lung for carbon monoxide; FVC: forced vital capacity; GERD: gastroesophageal reflux disease; ILD: interstitial lung disease; mRSS: modified Rodnan skin score; TLC: total lung capacity.
Effect modification by baseline FVC on association between CYC/MMF and lung outcomes
Table 2 presents stratified estimates for the association between CYC/MMF exposure at baseline and FVC % predicted at one year, using multivariate linear regression. In subjects with mild ILD, those who were exposed to CYC/MMF had a higher FVC at one year compared with unexposed subjects, by a difference of 8.49% predicted FVC (95% CI: 0.01–16.98%). In contrast, in subjects with moderate ILD, we were unable to establish a significant difference in FVC at one year between exposed and unexposed subjects.
Table 2.
Adjusted estimates for association between baseline CYC/MMF exposure and FVC % predicted at one year
| Estimate (β) | 95% CI | ||
|---|---|---|---|
| Mild ILD | |||
| Exposure to CYC/MMF | 8.49 | 0.01 | 16.98 |
| FVC (baseline) | 0.84 | 0.61 | 1.06 |
| DLCO | 0.01 | −0.09 | 0.12 |
| Disease duration | 0.57 | −0.48 | 1.63 |
| mRSS | 0.03 | −0.17 | 0.22 |
| Shortness of breath score | −0.70 | −1.64 | 0.24 |
| FVC × Exposure to CYC/MMF | 0.11 | −0.50 | 0.72 |
| Moderate ILD | |||
| Exposure to CYC/MMF | −2.04 | −10.39 | 6.31 |
| FVC (baseline) | 0.89 | 0.55 | 1.23 |
| DLCO | 0.10 | −0.11 | 0.31 |
| Disease duration | −0.32 | −1.85 | 1.22 |
| mRSS | −0.03 | −0.28 | 0.22 |
| Shortness of breath score | −0.23 | −1.28 | 0.83 |
| FVC * Exposure to CYC/MMF | −0.07 | −0.74 | 0.61 |
Refer to Table 1 legend for definitions and abbreviations. When only adjusted for baseline FVC (in interaction with exposure to CYC/MMF), the estimate for exposure to CYC/MMF was 5.06% (95% CI: –2.48–12.61%) in mild ILD and –5.39% (95% CI: –24.12–13.35%) in moderate ILD.
Figure 2 presents a forest plot of estimates obtained from sensitivity and secondary analyses. Using alternative FVC thresholds to categorize patients into milder and more severe lung disease, the difference in FVC between exposed and unexposed subjects was generally larger among those with milder disease (Fig. 2B). Similarly, when using data from the entire SSc-ILD cohort, although the mean FVC at one year did not differ between exposed and unexposed subjects (2.48% difference in predicted FVC, 95% CI: –2.55–7.50%), this difference was larger by 1.9% predicted (95% CI: –0.2–4.1%) for every 10 units increase in baseline % predicted FVC. The risk of clinically meaningful progression or death was lower among exposed subjects with higher baseline FVC (odds ratio 0.92, 95% CI: 0.82–0.99, for every unit increase in baseline % predicted FVC). However, we found no clear difference in DLCO at one and two years, regardless of baseline disease severity. Results from other sensitivity analyses were consistent with those from the primary analyses (Fig. 2A).
Fig. 2.
Forest plots displaying results obtained from sensitivity and secondary analyses for pulmonary function outcomes
Estimated mean differences in FVC and DLCO (% predicted) in subjects exposed to CYC/MMF at baseline compared with unexposed subjects are presented: (A) stratified according to whether the baseline FVC is > 85% (mild ILD) or ≤ 85% predicted (moderate ILD); and (B) stratified according to alternative FVC thresholds (above or below 100%, 90%, 80% and 70% predicted). HRCT: high-resolution computed tomography; ILD: interstitial lung disease.
Evolution of pulmonary function in mild SSc-ILD
Supplementary Table S1, available at Rheumatology online, presents the pulmonary function trajectories and other outcomes at one and two years. In patients with mild SSc-ILD, mean FVC and DLCO at baseline were 99.4% and 71.2%. Within this subgroup, none of those who were exposed to CYC/MMF experienced clinically meaningful progression over two years, whereas 18.5% and 24.6% of unexposed subjects experienced clinically meaningful progression at one and two years.
Supplementary Fig. S1, available at Rheumatology online, presents unadjusted Kaplan-Meier survival curves for the time to clinically meaningful progression, stratified according to baseline exposure to immunosuppressive drugs. Survival was not different according to exposure in subjects with mild ILD (log rank P = 0.114), but was lower among exposed subjects with moderate ILD (log rank P = 0.020). Adjusted Cox proportional hazard regression analysis could not be performed given the small number of subjects available for analysis beyond two years of follow-up.
Baseline predictors of clinically meaningful progression in unexposed mild SSc-ILD patients
Table 3 presents the baseline characteristics of the unexposed mild SSc-ILD cohort, stratified by the presence of clinically meaningful progression at two years. Progressors tended to have lower baseline DLCO values and a higher prevalence of pulmonary hypertension and traction bronchiectases, but fairly similar FVC, mRSS, shortness of breath scores and anti-topoisomerase I antibody prevalence compared with non-progressors.
Table 3.
Baseline characteristics of unexposed mild SSc-ILD cohort, stratified by clinically meaningful progression at two years
| Unexposed mild SSc-ILD | |||
|---|---|---|---|
| Non-progressors (n = 49) | Progressors (n = 16) | Difference (95% CI)a | |
| Demographics | |||
| Age, years | 55.1 (12.1) | 59.4 (12.0) | 4.3 (−2.8 to 11.4) |
| Female | 40 (82%) | 12 (75%) | −7% (−32% to 19%) |
| White | 36 (73%) | 13 (81%) | 8% (−17% to 32%) |
| Smoking, ever | 26 (54%) | 12 (75%) | 21% (−7% to 48%) |
| SSc clinical characteristics | |||
| Disease duration, years | 4.2 (1.8) | 3.3 (2.5) | −0.9 (−2.3 to 0.5) |
| Diffuse subtype | 30 (61%) | 7 (44%) | −17% (−48% to 13%) |
| mRSS (0–51) | 13.4 (11.2) | 11.6 (12.3) | −1.8 (−9.0 to 5.3) |
| Arthritis | 12 (25%) | 2 (12%) | −13% (−34% to 9%) |
| Inflammatory myositis | 5 (10%) | 0 (0%) | −10% (−19% to -1%) |
| GERD | 28 (60%) | 9 (56%) | −4% (−34% to 27%) |
| Pulmonary hypertension | 2 (7%) | 3 (27%) | 20% (−12% to 53%) |
| Disease activity (0–10) | 2.2 (2.0) | 3.2 (2.4) | 1.0 (−0.4 to 2.3) |
| Disease severity (0–10) | 2.7 (1.9) | 3.7 (2.6) | 1.0 (−0.5 to 2.4) |
| Disease damage (0–10) | 3.2 (2.2) | 3.6 (2.4) | 0.4 (−1.0 to 1.7) |
| ILD characteristics | |||
| FVC, % predicted | 99.2 (10.2) | 99.6 (10.2) | 0.4 (−5.6 to 6.5) |
| TLC, % predicted | 98.9 (10.4) | 100.8 (15.6) | 1.9 (−6.9 to 10.7) |
| DLCO, % predicted | 73.2 (18.8) | 63.6 (18.1) | −9.6 (−20.7 to 1.6) |
| Shortness of breath (0–10) | 1.3 (2.0) | 1.8 (2.3) | 0.5 (−0.8 to 1.8) |
| HRCT: | |||
| Ground glass, any | 18/28 (64%) | 4/5 (20%) | −44% (−99% to 10%) |
| Ground glass, moderate-severe | 3/28 (11%) | 0/5 (0%) | −11% (−23% to 1%) |
| Fibrotic interstitial changes, any | 18/27 (67%) | 7/8 (88%) | 21% (−12% to 54%) |
| Fibrotic interstitial changes, moderate-severe | 1/27 (4%) | 1/8 (13%) | 9% (−21% to 39%) |
| Honeycombing, any | 4/27 (15%) | 0/6 (0%) | −15% (−29% to 1%) |
| Honeycombing, moderate-severe | 0/27 (0%) | 0/6 (0%) | 0% (N/A) |
| Traction bronchiectasis, any | 3/28 (11%) | 4/7 (57%) | 46% (−3% to 96%) |
| Serologies | |||
| Anti-centromere | 13 (28%) | 3 (21%) | −7% (−34% to 21%) |
| Anti-topoisomerase 1 | 10 (22%) | 3 (21%) | −1% (−27% to 27%) |
| Anti-RNA polymerase III | 11 (24%) | 4 (29%) | 5% (−25% to 34%) |
| Anti-Ro52/TRIM21 | 13 (28%) | 5 (36%) | 8% (−24% to 38%) |
| Medications | |||
| Corticosteroids (any dose) | 2 (4%) | 4 (25%) | 21% (−3% to 45%) |
| Gastroprotective agents | 35 (71%) | 8 (50%) | −21% (−51% to 8%) |
Mean difference (95% CI) between non-progressors (reference) and progressors. Refer to Table 1 legend for definitions and abbreviations.
Discussion
In this study, we investigated whether use of immunosuppressive drugs was associated with better lung function in SSc patients with normal or mildly impaired lung function at baseline. We also aimed to determine whether this association differed between SSc patients with mild ILD vs those with greater lung functional impairment. Our results show that exposure to CYC or MMF was associated with improved FVC among subjects with mild ILD, defined as a baseline FVC over 85%. Additionally, we found that this difference in FVC between exposed and unexposed subjects was generally larger among those with milder disease compared with those with more severe disease.
Few studies have previously examined the effect of immunosuppressive drugs specifically in patients with mild ILD and yielded contradictory results [8, 13–17]. However, these studies were limited by their small sample sizes (n = 22–75), retrospective data collection, lack of adjustment for confounding, potential bias from missing data and, most importantly, lack of unexposed comparators, making it difficult to conclude on the predictive vs prognostic value of identified variables.
We did not observe a significant difference in DLCO at one and two years between exposed and unexposed subjects, in mild or moderate ILD. Although DLCO is considered by some as a better surrogate marker for severity of SSc-ILD compared with HRCT [18–20], this measure is also less specific as it also reflects any impairment in gas exchange (including pulmonary hypertension, which is also common in SSc). In our study cohort, 15% of subjects were recorded as having pulmonary hypertension according to the study physician and another 28% had an unknown or missing pulmonary hypertension status. As immunosuppressive drugs are generally considered ineffective for treating pulmonary hypertension [21], this may have explained why CYC/MMF showed no significant effect when DLCO was used as the outcome.
Finally, we observed that 23% of SSc-ILD subjects with an FVC >85% experienced clinically meaningful progression over two years. Wu et al. recently studied the predictors of ILD progression in mild ILD (defined as HRCT extent <20%) and identified lower peripheral oxygen saturation (SpO2) after 6-min walk test and history of arthritis (ever) as independent predictors for ILD progression [22]. In our study, we were unable to explore the effect of SpO2 after 6-min walk test (completed in 12% of subjects). We observed that in untreated mild SSc-ILD subjects, lower DLCO values at baseline tended to be associated with a higher risk of progression at two years. This is consistent with the observation that the most sensitive and earliest change in ILD is a reduction in DLCO [23]. Larger studies are needed to explore the risk factors for disease progression in mild SSc-ILD.
Limitations
This study has potential limitations. First, 54.1% of our subjects were excluded from the complete case analyses due to missing values in pulmonary function tests or other covariates. Although the demographic characteristics of excluded subjects were comparable to those of included subjects, the former had lower baseline FVC values, as well as higher shortness of breath and disease activity, severity and damage scores (Supplementary Table S2, available at Rheumatology online). Reassuringly, estimates obtained after incorporating multiple imputation, using data from the entire study cohort, were consistent with results from our primary analyses.
Second, CSRG medication data was only nominal for ‘current’ or ‘past exposure’. There were no details regarding specific start and stop dates, dose, intermittent exposure or total duration of treatment. Hence, we assumed that exposed subjects were exposed for a therapeutic amount of time and dose; and conversely, unexposed subjects were assumed to have remained unexposed for the subsequent time of follow-up. This could have led to drug exposure misclassification of person-time; however, this misclassification would likely be non-differential, leading to more conservative estimates.
Our study may also have been limited by residual confounding, as we were unable to adjust for disease severity and radiological pattern on HRCT or for trend in FVC prior to cohort entry, both reported to be important predictors of disease progression [11, 24–29] and both likely to influence drug prescription in clinical practice. Results were similar when adjusting for radiological features on HRCT, but this information was missing in approximately half of all patients. On the other hand, if there was residual confounding, we could also postulate that the protective drug effects observed among subjects with mild ILD represent conservative estimates.
In addition, we did not control for steroid exposure in our main analyses, as we only had current exposure, without dose or duration. We did find that steroid use correlated with use of CYC/MMF, and it is possible that some of the effects we attributed to CYC/MMF were in fact due to steroids. However, steroids have a limited usefulness in SSc, due to concerns regarding scleroderma renal crises. Also, in sensitivity analyses, controlling for the available steroid data, our conclusions remained unchanged.
Another potential limitation relates to the fact that we included subjects with up to seven years of SSc disease duration and no prior use of CYC/MMF. Although this criterion was chosen to mimic those used in the Scleroderma Lung Study [3, 5], it may have led to survival bias. Indeed, subjects with prevalent ILD must have survived up to seven years of disease without experiencing fatal ILD or requiring CYC/MMF treatment in order to be included in our cohort. However, sensitivity analyses restricted to subjects within three years of SSc disease onset led to estimates that were consistent in direction with our primary results.
Finally, it is worth noting that although the FVC improved in exposed mild SSc-ILD subjects, whether this translates into meaningful outcomes for patients—such as improved exercise tolerance, dyspnoea or health-related quality of life—remains to be defined. We also did not evaluate the risks of immunosuppressive drug exposure, such as drug-related toxicities, infections and hospitalizations, which are important to consider when weighing the benefits of preventive treatment approaches in a population with mild baseline disease.
In conclusion, our study conducted in a real-world setting found that in SSc patients recently diagnosed with ILD, CYC/MMF exposure was associated with a beneficial effect on FVC values at one year, specifically among those with a high baseline FVC. These results support our hypothesis that a window of opportunity exists for the treatment of SSc-ILD. Further research is urgently needed to define the predictors of disease progression among mild SSc-ILD patients, especially as there is growing interest in the therapeutic opportunities for the very early stages of SSc disease [8, 30].
Supplementary Material
Acknowledgements
We thank Mianbo Wang (Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada) for his time and assistance in extracting data from the Canadian Scleroderma Research Group registry database. We thank The Arthritis Society [S.H.], the Canadian Institutes for Health Research (CIHR) [S.H.], the Centre Hospitalier de l'Université de Montreal Foundation [S.H.], the Scleroderma Research Chair [S.H.], Sclérodermie Québec [S.H.], the University of Montreal Rheumatology Program educational grant [S.H.] and the Fonds de Recherche du Québec – Santé (FRQ-S) [M.H.] for their financial support. The Canadian Scleroderma Research Group (CSRG) is funded by the CIHR (grant #FRN 83518), the Scleroderma Society of Canada and its provincial Chapters, Scleroderma Society of Ontario, Scleroderma Society of Saskatchewan, Sclérodermie Québec, Cure Scleroderma Foundation, INOVA Diagnostics Inc. (San Diego, CA), Dr Fooke Laboratorien GmbH (Neuss, Germany), Euroimmun (Lubeck, Germany), Mikrogen GmbH (Neuried, Germany), FRQ-S, the Canadian Arthritis Network (CAN), and the Lady Davis Institute of Medical Research of the Jewish General Hospital, Montreal, QC.
Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript.
Disclosure statement: The authors have declared no conflicts of interest.
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