ILD Flashcards
What is the prevalence of anti centromere antibodies?
30-40%
What is the incidence of anti-topo-isomerase I antibodies
20-30%
MCID mRSS
3.5-5.3 units
Prevalence SSc in Europe and gender difference
7.2 per 100 000 individuals in Norway to 33.9 per 100 000 individuals in Italy, with almost 2-3 times higher prevalence of SSc in women.
Ten year survival in patients with SSc
eported at 65-73% in Europe and 54-82% in North America.
- Findings of tocilizumab in EUSTAR database
Post-hoc analysis using propensity score matching to comparing 93 SSc patients with 3 TCZ application to 93 SSc patients without TCZ patients. All patients fulfilled 2013 ACR-EULAR criteria and ≥17 years of ag. At one year follow-up a non -signicant between group difference in mRSS was -1.0 and for FVC 0.70 in favour of TCZ. Given the direction is consistent with phase II and phase III studies this generates hypothesis for potential effectiveness of TCZ in broader SSc population.
ESOS study design ( design)
Prospective observational study in 326 adult early dcSSc (<3 years) . Patients treated with HSCT, previous IMS treatment >4 months or use of any IMS other than MTX/MMF/cyclo a month preceding inclusion were excluded. Inclusion between 2010 and 2014. In this study physician and patient choose between MTX/MMF/ cyclo/ no IMS. During 24 month follow-up, 3 monthly check-up.
Outcome ESOS study: mRSS, FVC, subgroup difference
- at 24 months FU no difference in mRSS between groups (range between -2 to -4, with lowest effect in no IMS group). Given no IMS group is worst, data suggest starting ims early might be prognostically favorable.
- at 24 months after correction for confounders no difference in FVC between groups ( +3.3 CYC, +2.0 no IMS , +2.0 MMF, , -0.5 MTX)
- subset of SSc-ILD patients, with HRCT confirmed ILD OR FVC/DLCO <555% OR definte bibasal shadowing on X-ray effect were stronger ( +7.4% cyclo , +4.0% no IMS, + 3.2 MMF, -2.5% MTX)
- Cyclo group: more male patients, more cardiopulmonary involvement
No IMS: relatively longer skin fibrosis, more renal involvement; 10/56 ptn were started on IMS.
MTX: more muscle problems
- Definition progressive pulmonary fibrosis according to Official ATS/ERS/JRS/ALAT clinical practice guideline.
In patients with ILD of known or unknown etiology other than IPF who has radiological evidence of pulmonary fibers, PPF is defined as at least two of the following three criteria occurring within the past year with no alternative explanation:
- Worsening of respiratory symptoms
- Physiological evidence of disease progression (either of the following)
a. absolute decline in FVC >/ 5% within 1 year FU
b. Absolute decline in DLCO (corrected for HB) >/10% within 1 yr of FU - Radiological evidence of disease progression (one or more of the following)
a. increased extent or severity of transition bronchiectasis and bronchiolectasis
b. new ground glass opacity with traction bronchiectasis
c. new fine reticulation
d. increased extend or increased coarseness of reticular abnormality
e. new or increased honeycombing
f. increased lobar volume loss
Risk reduction of progression of ILD in Inbuild trial
2.4 times
According to recent (2023) EUSTAR analysis, what is effectiveness of cohort enrichment studies in clinical studies to include patients with progressive ILD (design/outcome(2objectives)/ results)
Design: Analysis on 2259 Adult SSc patients fulfilling ACR-eular 2013 criteria with HRCT-ILD
Patients fulfilling Focussed/SLS II/Scensics trial
a. 68% none of these criteria
b. 31.2% SCENCIS criteria
c. 5.8% SLS II
d. 1.5% focussced
Univariate analysis to assess likelihood to enrich cohort for progressive disease for known risk factors.
a. No single risk factor really enriches cohort: ATA, ACA< dcSSc, age, FVC, DLCO, male, disease duration, elvated CRP, NYHA, GERD. Of note, FVC<70% seems to enrich for patients improving in first year (let op: univaraat, dus mogelijk effect Rtx)
Multivariable logistic regression using simplified inclusion criteria, without correction for treatment, from following studies: simplified SLSII, Focussed, scensis trial (extensive disease on HRCT not included in this current study). To assess likelihood to enrich for progressive disease
a. Focussed criteria seem to enrich for progressive disease. Of note, in the eustar database these patients are not treated in first year and in 2nd year 80% received IMS treatment. In patients fulfilling SLS II , 31.8% received IMS and in 2nd year 40% IMS (in 35% newly introduced in 2nd year).
Major limitations study: no correction for treatment effects on natural disease course.
Findings hoffman 2021 Progressive ILD
SSc-ILD is progressing relatively slowly
Deleterious outcome in SSc-ILD is based on cumulative progression.
23-27% of patients with SSc-ILD experienced ILD progression at any time
67% of patients experience progression at any time over the mean 5-year follow-up period
Effect dose reduction in MMF in Scensis trial
Discontinuation during 52 weeks: nintedanib: 19.4% and placebo: 10.8%
≥1 dose reduction and/or treatment interruption: nintedanib 48.3%, plaebo: 12.2%
Adverse events in SSc-ILD similar across subgroups defined by age, sex, race, weight
Dose adjustment in MMF no influence on rate of decline in FVC. Suggests dose adjustment does not reduce efficicay of nintedanib. Does not mean that efficacy is influenced if you intiatie treatment at lower dose, because these adjustments were made during treatment. A dose finding study in patients with IPF identified nintedanib 150 mg two times per day as the optimal dose for reducitng the rate of decline in FVC.
IMS use in SSc-ILD and influence on FVC course in EUSTAR dabase, adler 2018
Large proportion of Ssc-ILD did not receive IMS despite having dcSSc (34% of patients), active scleroderma pattern on NCM (40% of patients) and Valentini disease activity index ≥3 (12% of patients). On average these patients have longer disease duration and show fewer signs of alveolitis on HRCT. These characteristics may suggest that the greatest decline in lung function has already happened and stabilisation of lung function in the absence of active inflammation is expected without any further IS medication, or they might represent patients with overall benign disease courses.
Association between QILD / QLF score and course FVC in focussed study (fu duration 48 weeks).
68/104 in TCZ and 68/106 in placebo group had ILD.
* Higher degrees of QILD scores were associated with increasing mRSS scores, anti-topo I antibody positivity, lower baseline FVC% and DLCO%, and higher QLF scores.
The mean ppFVC was significantly lower in patients with severe QILD (mean ±SD 73.6±12.9%) compared to those with
* minimal QILD (88.4±18.3%, p=0.01).
* mild QILD ( 85.4±13.1%, p=0.00)
* moderate QILD (81.1 ±14.4, p=0.01)
* TCZ group showed preservations of FVC. LSM of FVC% change was -0.1%. Difference between treatment groups was 6.2% (p<0.0001).
* At 48 weeks overall QILD scores for TCZ arm showed significant improvement (mean -1.8% (95% ci -3.8, 0.09) p=0.02). baseline Patients with >20% QILD showed the largest improvement of the subsets (mean -4.9 995% ci -8.5—1.2, p=0.01). In terms of fibrosis, there was a significant increase in QLF scores at 48 weeks in the placebo arm (mean 0.7995% ci 0.3, 1.20; p=0.00) that was not seen in the TCZ arm (mean -0.5(95% ci -1.3, 0.3], p=0.12).
Course FVC in FAsscinate/ Focussed
Fasscinate, II: 10% in TCZ group vs 23% in placebo group had ≥10% absolute decrease in FVC%.
Focussced, III: mean decline in TCZ -0.6% vs -4.0% in placebo group, p=0.0002).
* The preservation of FVC in the TCZ arm did not vary according to baseline QILD or QLF score, emphasizing the importance of early intervention to retard progression for those with even mild lung involvement
* In addition, the placebo group showed worsening lung fibrosis on HRCT scans at 48 weeks, whereas the TCZ arm showed attenuation of development of progressive fibrosis.
Proportion SSc-ILD in focussed
- ~65% of patients with early dcSSC ahd HRCT-defined ILD, with 77% of participants having >10% total lung involvement (as assessed by QILD)
Focussed population vs SLS II and SCENSIS
Population TCZ: early dcSSc patients with progressive skin disease and elevated acute-phase reactants. This cohort may represent an immunoinflammatory phase, rather than advanced stage fibrotic ILD studies in previous SSc-ILD trials. Four large prior studies (SLSI, SLSII, FAST, SCENSCIS) included patients with both lcSSc and dcSSc,with a median disease duration ≤7 years, and included patients who were categorized as having clinical ILD based on respiratory symptoms (grade ≥2 exertional dyspnea according to baseline Mahler Dyspnea index in SLS I and SLS II) and fibrosis (≥10% of lungs in the SCENSCIS). Participants in these trials had moderate-to-severe fibrotic disease:
* SLS II mean±SD QLF score 8.6 ±6.9%
* SCENSCIS mean ±SD visual fibrosis score 36.8±21.8 in treatment arm & 35.2±20.7 in placebo arm.
With exception of FAST trail (FVC 80.1% and 81.0% in treatment and placebo arms, respectively) participants in these studies demonstrated FVC% impairment: 68.1% in SLSI, 66.5% in SLSII and 72% in SENSCIS.
Interpretation GGO reduction on HRCT scan; implication SLS II
Ground-glass opacity in early SSc may represent either inflammation or fibrosis that is below the resolution of the HRCT technique at the level of intralobular septa and interstitium surrounding alveoli.
QGG reduced in both group by -2.56(cyclo) and -3.35(MMF), however the direction of change could have been progression of either inflammation or fine fibrosis to more obvious fibrosis rather than resolution to normal lung. Thus, no change or acute decreases in QLF appear to be more useful indicators of stabilization or improvement respectively, in ILD.
Qualitative changes in HRCT findings SLS I
QILD score decreased in cyclo group, while increased in placebo group
* Cyclo: -3.2% placebo: + 2.2% difference ~5% (p=0.03) in the whole lung
* Cyclo -3.9% placebo +4.2%, difference ~8% (p=0.0108) in the most severe lung lobe
* in cyclo arm verdeling van verandering in QGG and QLF nagenoeg gelijk, terwijl in plaebo arm QLF vnl toeneemt en QGG vnl afneemt.
* We observed no significant changes in QGG by treatment group, consistent with previous observations. On the other hand, we found that increasing QLF scores in the placebo arm were accompanied by a significant reduction in QGG scores in the most severe zone (figure 1E), consistent with the concept that GG opacities may represent early fibrosis, which, in the absence of effective treatment, progress to more clearly defined reticulations over time (see figure 2E-H). Reticulations scored as QLF may partially resolve into finer intralobular fibrosis with a radiographic appearance of GG opacity or possibly fully resolve into normal-appearing lung with active treatment. In contrast, directionally opposite changes in QGG and QLF scores in placebo patients, as illustrated in 1E&F may represent the transition from subresolution to more obvious fibrosis while mitigating the changes in QILD scores.
Meta-analyse effecicya of MMF vs Cyclo in SSc-ILd, ma et al 2021
- Included observational studies and RCTs studying efficacy of MMF vs cyclo in SSc-ILD with at least 6 months treatment published between 1990 and april2020.
- SLS I, 3 prospective, 2 retrospective studies. Mean age 43.5-54.1 years. Mean disease duration 2.5-7.6 years.
- FVC baseline ranged between 48-90% but in each study not different between MMF and cyclo group
- Pooled analysis on 6 studies with FVC : weighted minimal difference(95%CI) of FVC change in MMF groups compared to CYC group was -1.17(-2.713-0.373, p=0.137, I2=3.9%).
- Pooled analysis on 4 studies with DLCO: showed a weighted minimal difference of DLCO change in MMF groups vs CYC of 2.245(0.258-4.232, p=0.027, I2=48%). MMF seems to be slightly superior to CYC in terms of DLco improvement in our meta-analysis (P = 0.027), whereas the advantage of MMF over CYC on DLco improvement in the SLS I indicates no statistical significance. However, since there are only four studies that provided data on DLco change, the effectiveness of the meta-analysis is not sufficiently robust. Problem DLCO: also influenced by PAH.
Reasons not to use DLCO as outcome instrument according to overact filter 2.1 process
Compared to the FVC,
* DLco’s variability is larger
* reproducibility is less reliable, despite laboratory quality control procedures
* The DLco is a calculated measure: it is the product of measured Kco (the amount of carbon monoxide taken up in a known volume) and measured total alveolar volume as a results, measurement variation of either or both of these two measruements may impact its accuracy and reproducibility.
* DLco is subject to confounding due to pulmonary vascular disease in SSc and interpretation is challenging in patients with several pathological factors that impact the DLco (e.g. , SSc-ILD, co-occuring pulmonary hypertension, emphysametous changes from tobacco abuse).
Voorsepllende waarde NCM (5, jaar, bij 10 jaar)
Normale NCM & geen antistoffen: 1.3% & 1.6%
SSc patroon & geen Ab: 22.6% & 22.6%
Normale NCM en SSc Ab: 21.5% % 31.3%
SSc & Ab: 65.9 & 72.7%
MCID FVC
from pooled SLS I &SLS II population
* Improvement FVC: 3.0% - 5.3%
* Decrease Worsening: -3.0 to -3.3%
Study design FAST study
RCT
cycli i.v. + prednison alternated days 6 months followed by AZA (n=22) vs. placebo (n=23
Inclusion: SSc-ILD, without previous treatment with cycle, Gaza, high dose oral cortison
FVC baseline: 80
Results FAST study
difference between 2 arms adjusted for baseline FVC and treatment center revealed favorable outcome of FCV of -4.19%, p=0.08! (non significant)
Outcome SLS I study
Mean absolute difference in adjusted 12-month FVC% was 2.53% favoring CYC (P<0.03).
CYC improved dyspnea and quality of life compared to placebo.
Study design SLS I study
phase III, RCT
oral cycli 2 mg/m2/day vs placebo
12 months
n158.
Inclusion: SSc-ILD, disease duration ± 3 years, FVC baseline: 67-68%
Study design SLS II
Oral MMF 2dd1500 mg for 24 months (n-69) vs. oral cycle 2mg/kg/dag for 12 months followed by placebo for 12 months (n -73)
FVC baseline ± 66%
Results SLSII study
At 24 months
MMF +2.19%
Cyclo +2.88%
No significant difference
Quantitative ILD involvement in whole lung significantly reduced by an average of 2.51% over 24 months; no between group difference
