Abstract
Objective:
Tocilizumab has demonstrated lung function preservation in two randomized controlled trials in early systemic sclerosis (SSc). This effect has yet to be characterized in terms of quantitative radiographic lung involvement. In this post-hoc analysis, we assess tocilizumab’s impact on lung function preservation, stratifying treatment arms by the degree of radiographic lung involvement.
Methods:
The focuSSced trial was a phase 3, randomized placebo-controlled trial of tocilizumab in patients with SSc and progressive skin disease. Participants had baseline and serial spirometry along with high resolution chest CT at baseline and week 48. Quantitative interstitial lung disease and fibrosis were derived using computer software. We divided quantitative interstitial lung disease in mild (5-10%), moderate (>10-20%), or severe (>20%) categories.
Results:
Of 210 participants recruited in the trial, 136 [65%] had interstitial lung disease. The majority of these participants had moderate-to-severe involvement defined by >10% lung involvement (77%). The tocilizumab arm demonstrated preservation of forced vital capacity over 48 weeks (least squared mean change in %predicted = −0.1) compared to placebo (−6.3%). For mild, moderate, and severe QILD, the mean decline in the %pFVC in the tocilizumab arm at 48 weeks were −4.1, 0.7, and 2.1, and in the placebo group were −10.0, −5.7, and −6.7, respectively. Similar treatment-related preservation findings were seen independent of fibrosis severity.
Conclusion:
Tocilizumab in early SSc- associated interstitial lung disease with progressive skin disease stabilized forced vital capacity over 48 weeks, independent of the extent of quantitative radiographic interstitial lung disease or fibrosis.
Keywords: Clinical Trial, Tocilizumab, Systemic Sclerosis, Quantitative Interstitial Lung Disease, Quantitative Lung Fibrosis
Introduction
The majority of systemic sclerosis patients will develop interstitial lung disease (SSc-ILD) (1, 2). The SSc-ILD disease process usually proceeds through different phases—the initial phase is associated with high resolution chest computed tomography (HRCT) findings of predominantly ground glass opacity with minimal fibrotic changes (that has been considered by some to be immuno-inflammatory) followed by more dense fibrotic changes with a non-specific interstitial pneumonia pattern on HRCT, although some patients may present with findings of usual interstitial pneumonitis(3). Those at risk for progressive disease have an archetype: early, diffuse cutaneous systemic sclerosis (dcSSc), with elevated acute phase reactants like C-reactive protein (CRP) and topoisomerase-1 antibody positivity (4–7). Patients with these high-risk features, especially those with disease in the initial phase of development, represent an important target for early intervention as ILD is largely irreversible in SSc (4, 8).
Tocilizumab (TCZ) is an anti-IL 6 agent (IgG1 humanized anti-IL-6 receptor monoclonal antibody), approved for the use of rheumatoid arthritis, giant cell arteritis, juvenile idiopathic arthritis, Castleman’s disease, and other immune-mediated diseases. Two well-designed randomized controlled trials of TCZ in early dcSSc demonstrated a significant lung preservation effect in the treatment arm compared to placebo (PBO) (9, 10). This effect has yet to be characterized in terms of quantitative radiographic lung involvement.
In this post-hoc analysis, we comprehensively characterized the ILD participants in the focuSSced trial (10), assessed the relationship between degree of total lung involvement and fibrosis (using well-established quantitative HRCT measurements) and lung physiology, and evaluated TCZ’s treatment effect compared to PBO on FVC and quantitative HRCT. Investigating the treatment effects in terms of radiographic changes in this cohort at high risk for progression of ILD provides an important insight into disease pathophysiology and potential mechanisms of therapeutic benefit.
Patients and Methods
Study Design
This phase III trial (ClinicalTrials.gov, NCT02453256) was a multicenter, randomized, double-blind placebo-controlled trial with 1:1 randomization to active treatment (TCZ 162 mg subcutaneous injection/week) vs PBO for 48 weeks (10). Background immunosuppressive therapy was not allowed in the trial but escape therapy was allowed for prespecified skin and lung function progression, and SSc-related complications.
Participants
All participants met 2013 American College of Rheumatology/European League Against Rheumatism classification criteria, with disease onset <60 months from the onset of their first non-Raynaud’s Phenomenon sign or symptom, and had a modified Rodnan Skin Score (mRSS) between 10-35 units; all had early progressive skin disease with diffuse cutaneous distribution as the main goal of the trial was to see a beneficial impact of TCZ on the mRSS. Participants also had elevated acute-phase reactants (≥1 of the following: CRP >6mg/L, ESR >28mm/h, or platelet count >330 ×109/L) and active disease defined as >1 of the following at screening: disease duration ≤18 months, mRSS increase ≥3 units, or involvement of one new body area and mRSS increase ≥2 units, or involvement of two new body areas (each within the previous 6 months), and ≥1 tendon friction rub. The presence of lung disease was not required for enrollment. The study was approved by the institutional review boards of all participating sites, written informed consent was obtained from all participants and the study was conducted in compliance with the Helsinki Declaration.
Outcome Measures
Serial spirometry plus diffusing capacity for carbon monoxide corrected for hemoglobin (DLco) was conducted at weeks 8, 16, 24, 36, and 48, based on the American Thoracic Society/European Respiratory Society (ATS/ERS) Consensus Statement recommendations. Participants performed three to eight exhalations into a spirometer with the highest value recorded. Participants received a baseline and week 48 HRCT, completed at maximal inspiration. Images were acquired from 30 different multidetector CT scanner models from four manufacturers using a standardized procedure following strict quality control protocols. HRCT quantification was performed on all scans based on previous publications (11–13).
Quantitative ILD (QILD) refers to the summation of ground glass opacities, honeycombing, and fibrotic reticulation, while quantitative lung fibrosis (QLF) refers to the quantitative fibrosis (fibrotic reticulation) alone. Both scores range from 0-100% of the whole lung(14). All scans had QILD and QLF measurements; ILD was identified visually by a thoracic radiologist (J. G.) as the presence of ground-glass opacification and/or fibrosis with a basal predominance. Participants who had minimal interstitial changes without defined ILD were characterized as no ILD; these cases were screened for factors other than SSc-ILD and excluded (these included body habitus, atelectasis, bronchitis, aspiration, bronchiectasis). QILD cutoff points were set as minimal (≥5%), mild (5-10%), moderate (>10-20%), or severe (>20%) based on 1) a chest radiologist’s (J.G.) classification and 2) publication by Goh et al., where total lung involvement of >20% was associated with higher mortality in a longitudinal cohort(15). Cutoff points for QLF were set into tertiles given the range (0.1-18.5%) of involvement.
Statistics
Continuous and categorical variables were summarized using means and standard deviations (SD), and percentages, respectively. T test was used to compare baseline %pFVC by baseline QILD and QLF cutoffs. Spearman correlation coefficients were calculated for scatter plots of baseline %pFVC by numerical baseline QILD and QLF, separately. To assess how the baseline QILD or QLF affects the change of %pFVC over time, we fitted linear mixed effect models, with change of %pFVC as the outcome. Covariates included: 1) baseline %pFVC, 2) treatment arm, 3) study time points, 4) baseline QILD/QLF group, 5) interaction of baseline %pFVC and study time point, 6) interaction of treatment arm and study time point, 7) interaction of baseline QILD/QLF group and treatment arm, 8) interaction of baseline QILD/QLF group and study time point, 9) three-way interaction of treatment arm, study time point, and baseline QILD/QLF group. We obtained least squares means (LSM) from the models, and plotted the LSM to show the FVC change trend. No data were imputed. All analyses were done via SAS software (Version 9.4).
Results
Baseline characteristics of participants with ILD
Supplemental Figure 1 shows the distribution of patients as it relates to their treatment arm and baseline radiographic assessments. Two hundred and ten participants were randomized and received treatment: 106 to the PBO arm and 104 to the TCZ arm. Of these participants, 136 were confirmed by a thoracic radiologist to have ILD on HRCT done at baseline. Table 1 shows the baseline characteristics of the overall population (n= 210) compared to the subset of participants with ILD (n=136), which is further divided by treatment arm. Three participants had ILD based on baseline visual assessment of HRCT, however their percent quantity of ILD (including QILD and QLF) were missing. Compared to those without ILD, the remaining 133 participants with ILD had numerically lower %pFVC and %pDLco, higher CRP, and a greater percentage of anti-topoisomerase-1 antibody positivity. ILD participants had a mean (SD) %pFVC of 79.6 (14.5) and 18.7% (11.1) QILD with most of that being ground-glass opacities (14.9% (8.3)); QLF accounted for a mean (SD) of 3.0% (3.6)). There were no significant differences between TCZ and PBO arms in the ILD groups at baseline. (Table 1).
Table 1:
Baseline characteristics of the overall focuSSced population and those with ILD on HRCT
| All Patients N=210 |
ILD N=136 |
Tocilizumab N=68 |
Placebo N=68 |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Demographics | ||||||||||||
| Females, % | 81.4 | 79.4 | 77.9 | 80.9 | ||||||||
| Age, mean years (SD) | 48.2 | (12.4) | 48.1 | (12.9) | 47.6 | (12.5) | 48.7 | (13.3) | ||||
| Duration of SSc months, (SD) | 22.6 | (16.5) | 22.8 | (16.8) | 23.0 | (17.2) | 22.6 | (16.6) | ||||
| Disease Features | ||||||||||||
| Total mRSS, units (SD) | 20.3 | (6.8) | 20.8 | (7.0) | 20.7 | (6.8) | 20.9 | (7.2) | ||||
| CRP, mg/L, (SD) | 7.9 | (13.1) | 9.6 | (15.4) | 11.2 | (17.4) | 8.0 | (13.1) | ||||
| ANA positive, n/N (%) | 183/198 | (92.4) | 124/128 | (96.9) | 65/66 | (98.5) | 59/62 | (95.2) | ||||
| Anti-topoisomerase +, n/N (%) | 103/202 | (51.0) | 90/131 | (68.7) | 46/67 | (68.7) | 44/64 | (68.8) | ||||
| Anti-RNA polymerase +, n/N (%) | 35/202 | (17.3) | 19/131 | (14.5) | 13/67 | (19.4) | 6/64 | (9.4) | ||||
| Anti-centromere +, n/N (%) | 17/202 | (8.4) | 2/131 | (1.5) | 1/67 | (1.5) | 1/64 | (1.6) | ||||
| Baseline Pulmonary Function Assessments | ||||||||||||
| FVC, in ml, (SD) | 2996.7 | (836.8) | 2885.4 | (835.8) | 2826.8 | (873.7) | 2944.1 | (798.3) | ||||
| %pFVC, % (SD) | 82.1 | (14.8) | 79.6 | (14.5) | 77.7 | (13.9) | 81.5 | (14.9) | ||||
| %pDLCO, % (SD) | 75.6 | (18.9) | n=208 | 70.4 | (16.9) | n=135 | 68.7 | (16.8) | n=68 | 72.1 | (17.0) | n=67 |
| Baseline Quantitative ILD Measurements, Whole Lung %* | ||||||||||||
| HRCT QILD, % (SD) | 15.9 | (11.4) | n=202 | 18.7 | (11.1) | n=133 | 20.5 | (12.8) | n=67 | 16.8 | (8.8) | n=66 |
| GGO, % (SD) | 13.0 | (8.8) | n=202 | 14.9 | (8.3) | n=133 | 16.2 | (9.5) | n=67 | 13.6 | (6.7) | n=66 |
| QLF, % (SD) | 2.3 | (3.3) | n=202 | 3.0 | (3.6) | n=133 | 3.5 | (4.2) | n=67 | 2.5 | (3.0) | n=66 |
| HC, % (SD) | 0.4 | (1.2) | n=202 | 0.4 | (1.3) | n=133 | 0.5 | (1.5) | n=67 | 0.3 | (1.2) | n=66 |
Three subjects had ILD based on baseline visual assessment of HRCT, however their percent quantity of ILD (including QILD and QLF) were missing. None of the differences between tocilizumab and placebo are statistically significant at p< 0.05.
SSc= Systemic Sclerosis; mRSS= Modified Rodnan Skin Score; CRP= C-Reactive Protein; ANA= Antinuclear Antibody; FVC- Forced Vital Capacity; pFVC= Predicted Forced Vital Capacity; pDLco= Predicted Diffusing Capacity for carbon monoxide corrected for haemoglobin; HRCT = High resolution CT; QILD= Total ILD (ground glass opacities, honeycombing, reticulations) on computer quantification; GGO = Ground glass opacities; QLF= Lung fibrosis (reticulations) on computer quantification; HC = Honeycombing
Majority of ILD participants had moderate-to-severe whole lung involvement with limited fibrosis
The baseline QILD of 133 participants were stratified into 4 groups corresponding to minimal (≤5%), mild (>5-10%), moderate (>10-20%), and severe (>20%) lung involvement. The majority of participants (77%, or 102/133) with ILD had moderate or severe lung involvement, as defined by QILD of >10% (range 10.2 −52.6, Table 2). Higher degrees of QILD scores were associated with increasing mRSS, percentages of anti-topoisomerase-1 antibody positivity, lower baseline %pFVC and %pDLco, and higher percentages of QLF. Table 2 also shows ILD participants stratified by QLF into tertiles (0.1-1.0%, 1.1-2.7%, 2.8-18.5%), with approximately 2/3rds of participants having ≤2.8% fibrosis (89/133 or 67%). Similar to QILD, increasing QLF% was associated with higher percentages of anti-topoisomerase-1 antibody positivity and QILD, and lower baseline %pFVC and %pDLco.
Table 2:
ILD Participants Stratified by Quantitative Interstitial Lung Disease and Lung Fibrosis involving the Whole Lung
| ILD | Quantitative Interstitial Lung Disease (QILD) by Ascending Severity |
Quantitative Lung Fibrosis (QLF) by Ascending Severity |
||||||
|---|---|---|---|---|---|---|---|---|
| Severity Cut-Off | - | Minimal <5% |
Mild >5-10% |
Moderate >10-20% |
Severe >20% |
1st Tertile 0.1-1.0% |
2nd Tertile 1.1-2.7% |
3rd Tertile 2.8-18.5% |
| N | N=133* | N=6 | N=25 | N=54 | N=48 | N=45 | N=44 | N=44 |
| Demographics | ||||||||
| Females, % | 79.0 | 66.7 | 76.0 | 83.3 | 77.1 | 77.8 | 81.8 | 77.3 |
| Age, mean years (SD) | 48.0 (13.0) | 45.2 (16.6) | 45.5 (11.3) | 45.9 (13.3) | 52.1 (12.3) | 43.2 (12.7) | 48.5 (12.4) | 52.5 (12.3) |
| Duration of SSc months, (SD) | 22.9 (16.9) | 24.4 (13.5) | 22.3 (16.6) | 27.0 (17.2) | 18.5 (16.5) | 22.3 (13.5) | 26.5 (19.6) | 19.9 (16.9) |
| Disease Features | ||||||||
| Total mRSS, units (SD) | 20.8 (7.1) | 16.6 (7.3) | 18.8 (5.8) | 20.9 (7.6) | 22.3 (6.7) | 19.7 (6.9) | 20.9 (7.4) | 21.9 (6.8) |
| CRP, mg/L, (SD) | 9.8 (15.5) | 31.0 (39.6) | 5.4 (8.3) | 11.4 (16.8) | 7.5 (9.0) | 10.9 (18.7) | 11.5 (17.0) | 6.8 (9.1) |
| ANA positive, n/N (%) | 121/125 (96.8) | 6/6 (100) | 24/24 (100) | 48/50 (96.0) | 43/45 (95.6) | 42/43 (97.7) | 40/41 (97.6) | 39/41 (95.1) |
| Anti-topoisomerase +, n/N (%) | 88/128 (68.8) | 4/6 (66.7) | 15/24 (62.5) | 33/50 (66.0) | 36/48 (75.0) | 28/43 (65.1) | 26/41 (63.4) | 34/44 (77.3) |
| Anti-RNA polymerase +, n/N (%) | 19/128 (14.8) | 1/6 (16.7) | 3/24 (12.5) | 5/50 (10.0) | 10/48 (20.8) | 4/43 (9.3) | 9/41 (22.0) | 6/44 (13.6) |
| Anti-centromere +, n/N (%) | 2/128 (1.6) | 0/6 (0.0) | 1/24 (4.2) | 1/50 (2.0) | 0/48 (0.0) | 1/43 (2.3) | 1/41 (2.4) | 0/44 (0.0) |
| Baseline Pulmonary Function Assessments | ||||||||
| FVC, in ml, (SD) |
2881.4 (833.6) |
3483.3 (1079.0) |
3268.8 (1031.4) |
2945.7 (672.4) |
2532.1 (720.8) |
3216.4 (908.1) |
2817.5 (656.4) |
2602.7 (810.8) |
| %pFVC, % (SD) | 79.5 (14.5) | 88.4 (18.3) | 85.4 (13.1) | 81.1 (14.4) | 73.6 (12.9) | 84.8 (14.6) | 79.6 (13.9) | 74.0 (13.1) |
| %pDLCO, % (SD) | 70.4 (17.1); n=132 | 88.5 (19.7) | 85.3 (17.2) | 67.3 (12.9) | 63.6 (14.9); n=47 | 75.9 (17.4) | 70.9 (17.0) | 64.0 (14.9); n=43 |
| Baseline Quantitative ILD Measurements, Whole Lung %* | ||||||||
| HRCT QILD, % (SD) | 18.7 (11.1) | 4.0 (0.9) | 7.8 (1.4) | 14.5 (2.8) | 30.8 (8.6) | 9.8 (4.2) | 16.4 (5.6) | 30.1 (10.3) |
| GGO, % (SD) | 14.9 (8.3) | 3.7 (0.8) | 6.9 (1.2) | 12.3 (2.7) | 23.5 (7.2) | 8.9 (3.9) | 14.0 (5.4) | 22.0 (8.8) |
| QLF, % (SD) | 3.0 (3.6) | 0.3 (0.1) | 0.8 (0.6) | 1.5 (1.0) | 6.1 (4.5) | 0.6 (0.3) | 1.7 (0.4) | 6.8 (4.3) |
| HC, % (SD) | 0.43 (1.3) | 0 (0) | 0 (0) | 0.3 (0.9) | 0.8 (2.0) | 0.1 (0.5) | 0.3 (0.9) | 0.9 (2.0) |
Three subjects had ILD based on baseline visual assessment of HRCT, however their percent quantity of ILD (including QILD and QLF) were missing.
SSc=Systemic Sclerosis; mRSS= Modified Rodnan Skin Score; CRP= C-Reactive Protein; ANA= Antinuclear Antibody; FVC- Forced Vital Capacity; pFVC= Predicted Forced Vital Capacity; pDLco= Predicted Diffusing Capacity for carbon monoxide corrected for haemoglobin; HRCT = High resolution CT; QILD= Total ILD (ground glass opacities, honeycombing, reticulations) on computer quantification; GGO = Ground glass opacities; QLF= Lung fibrosis (reticulations) on computer quantification; HC = Honeycombing
QILD and QLF Inversely Correlates with the Forced Vital Capacity
Figure 1 demonstrates an inverse relationship between the baseline %pFVC and degree of QILD (Panel A); baseline %pFVC significantly declined with each escalating QILD cutoff point. The mean baseline %pFVC for those with severe QILD was significantly lower (mean 73.6, SD 12.9) when compared to those with minimal (mean 88.4, SD 18.3, p=0.01), mild (mean 85.4, SD 13.1, p=0.00), and moderate QILD (mean 81.1, SD 14.4, p=0.01). There is an inverse correlation between the baseline %pFVC and QILD, with a correlation coefficient of −0.36, p=0.00. Figure 1 also demonstrates a similar inverse relationship of the baseline %pFVC with QLF (Panel B), with the mean baseline %pFVC significantly higher in the first tertile compared to the third tertile (p=0.00). The Spearman correlation was also −0.36 (p=0.00).
Figure 1:
Relationship between forced vital capacity % predicted and increasing severity of baseline QILD (A ) and increasing severity of baseline QLF (B). FVC= Forced Vital Capacity, QILD= Quantitative Interstitial Lung Disease, QLF= Quantitative Lung Fibrosis
TCZ Stabilizes FVC Over 48 Weeks for Baseline Mild-to-Severe QILD and All Ranges of Baseline QLF
The TCZ arm demonstrated preserved %pFVC over 48 weeks: the least squared means (LSM) of FVC change was −0.1% for TCZ, and −6.3% for PBO. The difference between treatment group was 6.2% (P<0.0001). Figure 2 shows the mean trend over 48 weeks of the %pFVC change, accounting for covariates listed in methods; the results are separated by treatment arm (TCZ vs PBO) and stratified by the extent of QILD. As there were only 2 and 4 evaluable patients in the PBO and TCZ groups, respectively, with ≤5% QILD over 48 weeks, they were excluded from Figure 2. Specifically, those with >5% QILD in the TCZ group showed %pFVC stabilization over 48 weeks; this preservation was not influenced by the escalating degree of QILD involvement. For mild, moderate, and severe QILD, the mean change in the %pFVC in the TCZ arm at 48 weeks were −4.1 (SD: 2.5), N=11, 0.7 (SD: 1.9), N=19, 2.1 (SD: 1.6), N=26 and in the PBO group was −10.0 (SD: 2.6), N=11, −5.7 (SD: 1.6), N=26, −6.7 (SD: 2.0), N=16, respectively. A pairwise comparison at week 48 in the TCZ arm showed no significant differences between the mild, moderate, or severe QILD strata. Those with >5% QILD in the PBO arm showed worsening %pFVC decline, also with no significant pairwise differences in the trajectory of the decline by QILD severity.
Figure 2:
ILD participants showing a mean trend over time of forced vital capacity change by treatment and quantitative ILD of the whole lung. Note: <5% is removed from this model as there were only 2 evaluable patients in the placebo group and 4 evaluable patients in the treatment group with <5% QILD over 48 weeks. FVC= Forced Vital Capacity; ILD= Interstitial Lung Disease; QILD= quantitative ILD; PBO= Placebo; TCZ= Tocilizumab
Figure 3 shows a similar preservation effect in the TCZ arm, not present in the PBO arm when stratified by QLF severity. The mean trend over time of the %pFVC change, accounting for covariates listed in methods, separated by treatment arm (TCZ vs PBO) do not differ by the extent of QLF for either the TCZ or the PBO arms.
Figure 3:
ILD participants showing a mean trend over time of forced vital capacity change by treatment and quantitative lung fibrosis of the whole lung. FVC= Forced Vital Capacity; ILD= Interstitial Lung Disease; PBO= Placebo; TCZ= Tocilizumab
TCZ Stabilizes QILD and QLF Over 48 Weeks, for All Ranges of Baseline QILD and QLF
Table 3 reports QILD and QLF scores at baseline and 48-week follow-up by treatment arm (TCZ vs. PBO), and is stratified by the baseline QILD and QLF cutoff points. As expected, higher baseline QILD and QLF have higher QILD and QLF values at 48 weeks. At 48 weeks, the overall QILD for the TCZ arm showed a statistically significant improvement (mean change (95% CI) −1.8 (−3.5, −0.2), p=0.02). This benefit appears to be largely driven by those with the highest degrees of QILD at baseline; those with >20% QILD had the largest improvement of any of the subsets (−4.9 (−7.8, −1.9), p=0.01). In terms of fibrosis, there was a statistically significant increase in QLF scores at 48 weeks in the PBO arm (0.7 (0.3, 1.1), p=0.00) that was not seen in the TCZ arm (−0.5 (−1.1, 0.2), p=0.12). This decline in the PBO appears to be driven by worsening of QLF in the 1st and 2nd tertiles.
Table 3:
Quantitative ILD and Fibrosis Scores Comparing Baseline to 48 weeks
| Baseline Mean (95% CI) |
48 week Mean (95% CI) |
Change from Baseline Mean (95% CI)* |
||||
|---|---|---|---|---|---|---|
| Tocilizumab | Placebo | Tocilizumab | Placebo | Tocilizumab | Placebo | |
| Whole Lung QILD (TCZ n=55; PBO n=48) | ||||||
| Overall n=103 |
21.1 (18.2, 23.9) n=55 |
16.0 (14.2, 17.8) n=48 |
19.2 (16.7, 21.8) n=55 |
17.4 (15.4, 19.5) n=48 |
−1.8 (−3.5, −0.2) n=55, p=0.02 |
1.5 (−0.03, 3.0) n=48, p=0.13 |
| ≤5% n=4 |
3.9 (2.2, 5.5) n=3 |
4.3 (-) n=1 |
3.6 (0.3, 6.8) n=3 |
5.9 (-) n=1 |
−0.3 (−2.7, 2.1) n=3 |
1.6 (-) n=1 |
| >5-10% n=19 |
7.2 (6.3, 8.1) n=9 |
8.0 (7.2, 8.8) n=10 |
7.8 (5.5, 10.0) n=9 |
11.6 (7.5, 15.7) n=10 |
0.6 (−1.1, 2.3) n=9, p=0.82 |
3.6 (−0.07, 7.3) n=10, p=0.11 |
| >10-20% n=43 |
15.1 (14.0, 16.2) n=19 |
14.4 (13.4, 15.4) n=24 |
15.7 (13.2, 18.2) n=19 |
16.8 (14.6, 19.0) n=24 |
0.6 (−1.8, 2.9) n=19, p=0.57 |
2.4 (0.5, 4.3) n=24, p=0.08 |
| >20% n=37 |
33.2 (30.1, 36.2) n=24 |
25.8 (23.2, 28.4) n=13 |
28.3 (25.1, 31.5) n=24 |
24.0 (19.3, 28.7) n=13 |
−4.9 (−7.8, −1.9) n=24, p=0.01 |
−1.9 (−5.2, 1.5) n=13, p=0.39 |
| Whole Lung QLF (TCZ n=55; PBO n=49) | ||||||
| Overall n=104 |
3.7 (2.7, 4.7) n=55 |
3.0 (1.5, 3.0) n=49 |
3.3 (2.5, 4.1) n=55 |
3.0 (2.1, 3.9) n=49 |
−0.5 (−1.1, 0.2) n=55, p=0.12 |
0.7 (0.3, 1.1) n=49, p=0.00 |
| 1st Tertile n = 35 |
0.6 (0.4, 0.7) n=15 |
0.0.6 (0.5, 0.7) n=20 |
0.7 (0.4, 0.9) n=15 |
1.1 (0.8, 1.4) n=20 |
0.09 (−0.1, 0.3) n=15, p=1.00 |
0.5 (0.1, 0.8) n=20, p=0.00 |
| 2nd Tertile n = 36 |
1.7 (1.5, 1.9) n=18 |
1.7 (1.5, 1.9) n=18 |
1.7 (1.2, 2.2) n=18 |
3.1 (2.2, 3.9) n=18 |
0.01 (−0.6, 0.6) n=18, p=0.42 |
1.4 (0.7, 2.1) n=18, p=0.00 |
| 3rd Tertile n = 33 |
7.6 (5.8, 9.3) n=22 |
6.3 (3.7, 8.8) n=11 |
6.3 (4.9, 7.7) n=22 |
6.4 (3.1, 9.7) n=11 |
−1.3 (−2.9, 0.4) n=22, p=0.21 |
0.1 (−1.0, 1.3) n=11, p=1.00 |
Negative score denotes improvement; (-) indicates 95% CI cannot be calculated as n=1. All P values were obtained from Wilcoxon signed rank test.
CI=Confidence Interval; QILD= Total ILD (ground glass opacities, honeycombing, reticulations) on computer quantification; QLF= Lung fibrosis (reticulations) on computer quantification
QILD is missing n=33: 19 dropped out between week 0 and 48 (7 in TCZ arm, 12 in PBO arm) and 14 were active through week 48, but had missing data at week 48 (6 in TCZ arm, 8 in PBO arm).
QLF is missing n=32: 19 dropped out between week 0 and 48 (7 in TCZ arm, 12 in PBO arm) and 13 were active through week 48, but had missing data at week 48 (6 in TCZ arm, 7 in PBO arm).
Discussion
In a Phase 2 trial (9), TCZ showed preservation of FVC compared to the PBO group in a population of early dcSSc; fewer patients in the TCZ arm had a decline in the percent predicted FVC (%pFVC): 10% in the TCZ group compared to 23% in the PBO group had ≥10% absolute decrease in the %pFVC. Based on these preliminary findings, focuSSced (10) trial was designed in early dcSSc, which replicated the effect of lung function preservation over 48 weeks: the mean decline in the TCZ group was −0.6% and −4.0% in PBO, p=0.002. In our current manuscript, we performed a post-hoc analysis using the individual patient data from the focuSSced trial and showed that approximately 65% of patients with early dcSSc have HRCT-defined ILD, with 77% of participants having >10% total lung involvement (as assessed by QILD). The preservation of FVC in the TCZ arm did not vary by the baseline degree of QILD or QLF, emphasizing the importance of early intervention to retard progression for those even with mild lung involvement. In addition, PBO arm showed worsening of lung fibrosis on HRCT at 48 weeks whereas TCZ attenuated the development of progressive fibrosis.
Our population in the focuSSced trial included an at-risk group for progressive ILD – early dcSSc with progressive skin disease and elevated acute phase reactants. This cohort may represent an immuno-inflammatory phase, rather than advanced-stage fibrotic ILD studied in previous SSc-ILD trials. Four large prior studies (e.g., the Scleroderma Lung Study I(16) and II(17), FAST(18), and the SENSCIS(19) trials) included participants with both limited and diffuse cutaneous SSc, with a median disease duration of ≤ 7 years, and enriched for clinical ILD based on respiratory symptoms (at least grade 2 exertional dyspnea according to baseline Mahler Dyspnea Index in the SLS-I and SLS-II studies), and fibrosis (≥10% of the lungs) in the SENSCIS trial(4, 20, 21). Participants in these trials had moderate-to-severe fibrotic disease: SLS-II had an average (SD) QLF of 8.6% (6.9) and SENSCIS reporting a visual fibrosis score of 36.8 (21.8) in the treatment arm and 35.2 (20.7) in the PBO arm(17, 19). With the exception of the FAST trial (%pFVC of 80.1% and 81.0% in the treatment and PBO arms, respectively), the studies’ participants had %pFVC impairment: 68.1% in SLS-I, 66.5% in SLS-II, and 72% in SENSCIS(16, 17, 19).
Placebo-controlled trials and observational cohort studies inform our understanding of the natural progression of SSc-ILD; our data have an important role in understanding the pathogenesis of SSc-ILD progression in our enriched group(22–26). The resulting average rate of decline (SD) of FVC in the focuSSced PBO group was 228.2 mL (394.2) over 48 weeks, or a p%FVC of about 6.5% and considerably higher than those previously reported: the FAST trial(18) had an average decline of 3.0%, which was similar to that of the SLS-I trial (2.6%), and the SENSCIS cohort showed a decline of 2.6%, or 93.3 mL (13.5) over 52 weeks(16, 19). As such, our current analysis may influence trial design by providing a template to target early ILD, where the participants may have none-to-minimal respiratory symptoms, and enrich for progressive fibrotic ILD where treatment impact may be easier to detect(27).
Considerable variability in screening for SSc-ILD with HRCT still exists (28). There is increasing consensus that all patients with systemic sclerosis receive screening with HRCT(29). Our data demonstrate the value of obtaining HRCT at the time of diagnosis: PFTs are not sensitive enough to accurately assess the presence of ILD and delays in treatment initiation may lead to irreversible disease(21, 30). Recently, Fleischner Society Writing Committee for Position Paper on interstitial lung abnormalities published consensus statement on interstitial lung abnormalities (ILAs)(31). They acknowledged that abnormalities identified during screening for ILD in high-risk groups (e.g., those with systemic sclerosis) are not considered as ILAs because they are not incidental(31). Analysis of our data shows that participants with >5% QILD involvement (majority of whom had involvement of their lower zones) was associated with a large decline in FVC% in the PBO group over 48 weeks, that mirrored in those with >10% QILD in the PBO group, highlighting the need for universal screening with HRCT in early dcSSc.
A unified treatment algorithm does not yet exist for SSc-ILD. Recent published work has established evidence-based consensus statements on medical management of SSc-ILD; however these do not address the varying subsets of SSc-ILD severity that impact clinical treatment decisions in practice(4, 20, 21). Our treatment algorithm divides patients into subclinical ILD (those with minimal ILD and preserved lung function) and clinical ILD (those with moderate-to-severe ILD and/or decline in PFTs). Based on current data, we propose to treat those with subclinical ILD but with at-risk features(4, 20, 21). As evidence accumulates for treatment effects in subsets of SSc-ILD, practice guidelines may favor targeted immunomodulatory therapies in early disease vs. anti-fibrotic therapy in later disease.
Strengths of our analysis include well-characterized data from a clinical trial and utilization of a well-established quantitative lung disease program to provide finer granularity for understanding TCZ’s lung preservation effect. This study serves as an example of the use of quantitative HRCT measurements in understanding SSc-ILD pathophysiology and its response to treatment(11, 32).
The analysis is not without limitations. First, the analysis is post-hoc and should be considered as hypothesis generating. Second, while the reduction in vital capacity reflects having fewer functional alveolar units(33), it is an indirect measurement of the flow-resistive properties of the lung(34) and other factors in early SSc may confound the results (e.g., hide-bound chest thickness can cause thoracic restriction, poor patient effort, an inability to form a tight seal around the mouthpiece). This was addressed by standardizing spirometry in the clinical trial. Finally, the minimal QILD group (<5%) has too few patients to establish any meaningful assumptions. Nevertheless, as the field of quantitative radiomics advances its ability to reliably identify interstitial disease changes this small, even this low percentage of lung involvement may prove to have clinical implications.
In conclusion, early dcSSc is associated with high prevalence of ILD, with 77% having moderate-to-severe ILD (defined as QILD>10%). TCZ was effective in preserving the lung function, irrespective of the degree of QILD and QLF at baseline. This likely represents targeting of the immuno-inflammatory, early fibrotic phase of the disease(35) and may be a window of therapeutic opportunity to preserve lung function in early dcSSc. We also highlight the natural history of early ILD that may serve as a template for other fibrotic diseases.
Supplementary Material
Acknowledgements:
We thank the sites and the patients who participated in the trial.
We also thank the focuSSced investigators from around the world:
Argentina: Eleonora Lucero, Bernardo Pons-Estel, Mariano Rivero, Guillermo Tate
Belgium: Vanessa Smith, Ellen De Langhe
Bulgaria: Rasho Rashkov, Anastas Batalov, Ivan Goranov, Rumen Stoilov
Canada: James Dunne, Sindhu R. Johnson, Janet E. Pope
Croatia: Dušanka Martinović Kaliterna
Denmark: Mette Mogensen, Anne Braae Olesen
France: Yannick Allanore
Germany: Joerg Christoph Henes, Ulf Müller-Ladner, Gabriela Riemekasten, Alla Skapenko
Greece: Panayiotis Vlachoyiannopoulos
Hungary: Emese Kiss, Tünde Minier
Italy: Lorenzo Beretta, Elisa Gremese, Marco Matucci-Cerinic, Gabriele Valentini
Japan: Yoshihide Asano, Tatsuya Atsumi, Hironobu Ihn, Tomonori Ishii, Osamu Ishikawa, Masataka Kuwana, Yoshihito Shima, Hiroki Takahashi, Kazuhiko Takehara, Yoshiya Tanaka, Yoshioki Yamasaki
Lithuania: Loreta Bukauskiene, Irena Butrimiene
Mexico: Gabriel Medrano Ramirez, Cesar Ramos-Remus, Tatiana Sofia Rodriguez Reyna
Netherlands: Jeska de Vries-Bouwstra, Jacob M. van Laar
Poland: Bogdan Batko, Slawomir Jeka, Eugeniusz Kucharz, Maria Majdan, Marzena Olesinska, Zaneta Smolenska
Portugal: Jose Alves, Maria Santos
Romania: Carmen Marina Mihai, Simona Rednic
Spain: Ivan Castellvi Barranco, Francisco Javier Lopez Longo, Carmen Simeon Aznar, Patricia Carreira
Switzerland: Oliver Distler, Ulrich A. Walker
United Kingdom: Emma Derrett-Smith, Bridget Griffiths, Neil McKay
United State: Jacob Aelion, Michael Borofsky, Roy Fleischmann, Joseph Z. Forstot, Suzanne Kafaja, M. Faisal Khan, Michael D. Kohen, Richard W. Martin, Fabian Mendoza-Ballesteros, Alireza Nami, Shirley Pang, Grissel Rios, Robert Simms, Keith Michael Sullivan, Virginia D. Steen
Funding: Dr. Roofeh was funded by the NIH/NIAMS T32 grant (AR007080). Dr. Khanna’s work was supported by the NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases (K24-AR-063129 & 1R01-AR070470-01A1).
Conflict of interest: Dr. Khanna reports grants and personal fees from Bristol Meyer Squib, during the conduct of the study; grants from NIH, grants from Immune Tolerance Network, grants and personal fees from Bayer, grants from Bristol Meyer Squib, grants from Horizon, grants from Pfizer, personal fees from Acceleron, personal fees from Acetlion, personal fees from Amgen, personal fees from Blade Therapeutics, personal fees from Boehringer Ingelheim, personal fees from CSL Behring, personal fees from Corbus, personal fees from Cytori, personal fees from Galapagos, personal fees from Genentech/Roche, personal fees from GSK, personal fees from Horizon, personal fees from Merck, personal fees from Mitsubishi Tanabe Pharma, personal fees from Regeneron, personal fees from Sanofi-Aventis, personal fees from United Therapeutics, other from Impact PH, personal fees from Eicos Sciences, Inc, personal fees and other from CiviBioPharma/Eicos Sciences, Inc., outside the submitted work.
Dr. Goldin reports other from MedQIA LLC, outside the submitted work.
Dr. Kim reports other from MedQIA, LLC. In addition, Dr. Kim has a patent US-2015-0324982-A1(Scores of Quantitative Interstitial Lung Disease) pending.
Dr. Lin reports other from Genentech, during the conduct of the study; other from Genentech, outside the submitted work; and Dr. Lin owns stock in Roche.
Dr. Furst reports grants and personal fees from Corbus, grants and personal fees from CSL Behring, grants and personal fees from Galapagos, grants and personal fees from Gilead, grants from GSK, grants from Kadmon, grants from PICORI, grants and personal fees from Pfizer, grants and personal fees from Talaris, personal fees from Abbvie, personal fees from Amgen, personal fees from Novartis, personal fees from Roche/Genentech, personal fees from Boehringer Ingelheim, personal fees from Speakers Bureau, outside the submitted work.
Dr. Denton reports personal fees from Actelion, grants and personal fees from GlaxoSmithKline, personal fees from Sanofi, grants and personal fees from Inventiva, personal fees from Boehringer Ingelheim, personal fees from Roche, grants and personal fees from CSL Behring, personal fees from Corbus, personal fees from Acceleron, personal fees from Horizon, during the conduct of the study.
Dr. Roofeh and Suiyuan Huang have nothing to disclose.
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