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Progression RA-ILD Poster ACR 2016 (Final Version)
- 1. *Values in table are median (interquartile range)
Abbreviations: Diffusing capacity for carbon monoxide (DLCO),), forced expiratory volume in 1 second (FEV1), forced
vital capacity (FVC), pulmonary function test (PFT), total lung capacity (TLC)
*Values in table are mean (±standard deviation) or n (%) unless otherwise specified
Abbreviations: Anti-citrullinated protein antibody (ACPA), number (n), high-resolution computed tomography (HRCT),
interstitial lung disease (ILD), rheumatoid arthritis (RA), rheumatoid factor (RF), nonspecific interstitial pneumonia
(NSIP), organizing pneumonia (OP), usual interstitial pneumonia (UIP)
All models adjusted for age at ILD diagnosis and sex. *Per 10-unit increase. †Per 10-unit decrease **Developed
pulmonary hypertension during follow-up. ***Per 10% decrease in first 6 months of follow-up. ††Having TTE
related to suspicion for pulmonary hypertension, not causation.
Progressive Decline of Lung Function in Rheumatoid Arthritis Associated
Interstitial Lung Disease
Percent Progression in 159 patients by type of ILD DiscussionPercent Progression in 167 patients with RA-ILD
References
Methods
Characteristics of 167 Patients with RA-ILD
Risk Factors for Progressive Lung Function Decline
© 2016 Mayo Foundation for Medical Education and Research
Jorge A. Zamora-Legoff1, Megan L. Krause1, Cynthia S. Crowson1,2, Jay H. Ryu3, Eric L. Matteson1,4
1Division of Rheumatology, Mayo Clinic, Rochester, MN; 2Division of Biomedical Statistics and Informatics
Mayo Clinic, Rochester, MN; 3Division of Pulmonary and Critical Care Medicine
Mayo Clinic, Rochester, MN; 4Division of Epidemiology, Mayo Clinic, Rochester, MN
Pulmonary Function in Percent Predicted by Type of ILD in
167 Patients with RA-ILD
1. Saketkoo LA, Mittoo S, Huscher D, Khanna D, Dellaripa PF, Distler O, et al. Connective tissue disease related
interstitial lung diseases and idiopathic pulmonary fibrosis: provisional core sets of domains and instruments for
use in clinical trials. Thorax. 2014;69(5):428-36.
2. Lee HK, Kim DS, Yoo B, Seo JB, Rho JY, Colby TV, et al. Histopathologic pattern and clinical features of
rheumatoid arthritis-associated interstitial lung disease. Chest. 2005;127(6):2019-27.
• In this study of the clinical course of pulmonary disease in a large single-
center cohort of patients with RA-associated ILD, progressive decline of
pulmonary function is common and typically worse in patients with UIP
than those with NSIP.
• PFT measures at baseline were similar among the subtypes of ILD with
the notable exception of DLCO which was lowest in UIP when compared
to both NSIP and OP.
• Patients who suffer greater loss of pulmonary function within the first six
months of diagnosis progress earlier than those who remain relatively
stable in the initial period following diagnosis. A lower pulmonary reserve
at time of ILD diagnosis as measured by DLCO and FVC increased the
risk of progression.
• Overall, the present findings suggest that baseline and 6 month changes
in pulmonary function in FVC are sensitive predictors for progressive and
significant loss of pulmonary function. Patients with UIP were more likely
to progress to a DLCO lower than 40 percent predicted than those with
NSIP.
Conclusions
• In this largest ever study of progression of pulmonary disease as
assessed by both FVC and DLCO pulmonary function measures in
patients with RA-ILD in long term follow-up, progressive loss of pulmonary
function was common and generally worse in patients with UIP than NSIP.
• By 5 years after ILD diagnosis, 40% of patients progressed to severe
pulmonary impairment by DLCO, 22% by FVC and a third of patients
required supplemental oxygen at rest.
• A lower baseline in both DLCO and FVC increased the risk of progression
and higher rates of change in the first 6 months increased the risk of
severe pulmonary impairment over time.
• Predictors of progression in patients with RA-ILD may be used to aid
clinicians in identifying that subset of patients who are at highest risk for
progression of ILD and aiding management decisions, and serve as a tool
for counseling both patients and their families.
• Study Population: Study subjects were identified through a unified single
center electronic medical record system using international diagnosis codes
for ILD with diagnosis occurring between January 1, 1998 and December
31, 2014. All identified cases that fulfilled the 1987 American College of
Rheumatology criteria for RA, with a minimum of 4 weeks follow-up, chest
HRCT, and at least 1 PFT were manually reviewed for ILD diagnosis
verification.
• Data Collection: PFT results were recorded in both volume (liters) and
percent predicted values and abstracted between 1 year prior to ILD
diagnosis and 10 years after ILD diagnosis. All PFTs in the 12 months
before or after ILD diagnosis and the first PFT for each subsequent follow-
up year were included. Transthoracic echocardiography examinations (TTE)
were manually reviewed for the presence of PH with a definition of
estimated right systolic ventricular pressure greater than 35 mmHg. RA
therapies and disease severity indicators were also collected by manual
record review.
• Statistical Analysis: Descriptive statistics (means, percentages, etc.) were
used to summarize the data. Comparisons between groups were performed
using Chi-square and rank sum tests. Progression was defined as the first
time a DLCO less than 40 percent predicted (or those too ill to perform the
DLCO) and/or those with FVC less than 50 percent predicted (severe
restriction). Time to progression was analyzed using the Kaplan-Meier
method and Cox models adjusted for age and sex. PH was modeled using
time-dependent covariates. Medications for RA were divided into distinct
groups and were analyzed using time-dependent covariates that started
when the medication was first used and stopped 30 days after the
medication was discontinued to allow for a wash-out period. Six month rate
of change in DLCO and FVC was estimated using the PFT measures
closest to ILD diagnosis (within ± 6 months) and closest to 6 months (up to
one year) after ILD diagnosis. Six month rate of change was calculated as
the absolute change in percent predicted DLCO or FVC between these 2
measures divided by the number of days between the measures and
multiplied by the number of days in 6 months to ensure comparability across
patients. Non-linear effects were examined using smoothing splines.
• Background: Currently, there are only limited data on rates of change
for lung disease in patients with RA-ILD, and uncertainty about which
outcome measures are best to assess progression (1). Clinical
evaluation and histopathological sampling along with high resolution
computed tomography (HRCT) is sensitive for detection and
classification of ILD, while pulmonary function testing (PFT) may be
better suited for assessing progression (2).
• Objective: The aim of this study is to utilize a large single center cohort
of patients with RA associated ILD to describe the progression of
pulmonary disease using measures of pulmonary physiology.
Background & Objective
Results
• 40% of patients developed DLCO <40% predicted and 22% developed
FVC <50% predicted by 5 years after ILD diagnosis.
• Risk factors for DLCO progression were usual interstitial pneumonia
(UIP) vs. nonspecific interstitial pneumonia (NSIP) (hazard ratio [HR]:
3.29; 95% confidence interval [CI]: 1.28, 8.41).
• Lower percent predicted DLCO and FVC at baseline increased the risk
for progression to DLCO<40% and FVC<50% predicted, and higher
rates of change in the first 6 months also increased the risk of
progression.
PFT (% predicted) UIP NSIP OP p-value
Baseline (±6 months)
TLC
FVC
FEV1
DLCO
70 (62, 79)
69 (59, 85)
70 (59, 84)
52 (38, 63)
72 (63, 81)
75 (59, 91)
71 (54, 91)
57 (45, 71)
94 (88, 97)
70 (57, 75)
52 (35, 69)
71 (67, 79)
0.021
0.70
0.14
0.006
Change in first 6 months
TLC
FVC
FEV1
DLCO
-0.8 (-7.1, 5.0)
1.5 (-3.9, 5.6)
-0.7 (-4.4, 4.4)
-2.2 (-7.0, 3.8)
1.8 (-5.2, 5.4)
-0.3 (-7.8, 5.2)
1.0 (-7.5, 6.7)
2.3 (-3.6, 8.1)
-10.8
-9.1 (-13.5, -4.6)
-9.8 (-22.8, 3.1)
-13.7 (-21.5, -5.9)
0.32
0.16
0.76
0.040
Change over all follow-up*
TLC
FVC
FEV1
DLCO
-0.1 (-0.6, 0.1)
-0.2 (-0.5, 0.1)
-0.2 (-0.4, 0.0)
-2.1 (-4.5, -0.9)
0.0 (-0.1, 0.5)
-0.2 (-0.5, 0.2)
-0.2 (-0.4, 0.1)
-0.9 (-2.7, 0.9)
-0.2 (-0.2, 0.1)
0.0 (0.0, 0.2)
0.1 (-0.1, 0.2)
-0.3 (-3.3, 1.2)
0.20
0.37
0.18
0.017
Characteristic NSIP
(n=70)
UIP
(n=89)
OP
(n=8)
Total*
(n=167)
Age at ILD diagnosis, years 67.3 (±9.9) 68.2 (±9.7) 56.2 (±8.9) 67.3 (±10.0)
Age at RA diagnosis, years 59.5 (±14.4) 59.5 (±12.3) 50.1 (±10.7) 59.0 (±13.2)
Ethnicity, Caucasian (n, %) 68 (97%) 84 (97%) 7 (88%) 159 (97%)
Sex, female (n, %) 37 (53%) 40 (55%) 4 (50%) 81 (49%)
Ever Smoker 40 (57%) 58 (65%) 7 (87%) 105 (62%)
Length of follow-up from ILD
diagnosis, years, median (range)
4.3 (0.1 –
13.4)
3.7 (0.1 –
14.8)
3.7 (0.1 –
8.8)
3.3 (0.1 –
14.8)
RA disease duration at ILD
diagnosis, years, median (range)
3.6 (-10.9 –
48.1)
5.4 (-9.8 –
43.0)
2.4 (-1.7 –
19.1)
4.2 (-10.9 –
48.1)
RF positive, n positive/ n tested (%) 56 / 68 (82%) 74 / 87 (85%) 4 / 8 (100%) 134 / 163
(82%)
ACPA positive, n positive/ n tested
(%)
51 / 64 (80%) 47 / 59 (80%) 3 / 6 (50%) 101 / 129
(78%)
Erosive disease (n, %) 16 (23%) 22 (25%) 3 (38%) 41 (25%)
Extra-articular manifestations other
than ILD (n, %)
31 (44%) 38 (43%) 4 (50%) 73 (44%)
Rheumatoid nodules 16 (23%) 25 (28%) 1 (13%) 42 (25%)
Severe extra-articular
manifestations other than ILD (n, %)
4 (6%) 6 (7%) 2 (25%) 12 (7%)
Emphysema on chest HRCT 8 (11%) 13 (15%) 1 (13%) 22 (13%)
Required supplemental oxygen at
ILD diagnosis (n, %)
6 (9%) 17 (19%) 0 (0%) 23 (14%)
Oxygen requirement at last visit
(liters/minute)
3.0 (±2.1) 2.7 (±1.2) 3.0 (±1.4) 2.8 (±1.5)
Risk Factor
DLCO < 40% predicted FVC < 50%
Hazard ratio
(95% CI)
P-value Hazard ratio
(95% CI)
P-value
Age * 1.26 (0.79, 1.98) 0.33 1.06 (0.61, 1.82) 0.84
Male sex 1.75 (0.74, 4.10) 0.20 0.98 (0.33, 2.92) 0.97
Ever smoker 0.35 (0.14, 0.85) 0.021 0.45 (0.15, 1.47) 0.20
Emphysema 1.34 (0.39, 4.57) 0.64 0.52 (0.07, 4.04) 0.53
RF or ACPA positive 2.61 (0.35, 19.57) 0.35 0.51 (0.11, 2.33) 0.38
ESR (mm/1hr) * 1.04 (0.86, 1.25) 0.71 0.83 (0.58, 1.17) 0.28
CRP (mg/L) * 0.98 (0.79, 1.21) 0.82 0.74 (0.37, 1.49) 0.40
Rheumatoid nodules 1.00 (0.40, 2.53) 0.99 -- 0.99
Severe extra-articular
manifestations
-- 0.99 -- 0.99
UIP vs NSIP 3.29 (1.28, 8.41) 0.013 0.86 (0.27, 2.73) 0.79
FVC percent predicted† 1.25 (0.97, 1.64) 0.087 2.38 (1.37, 4.17) 0.002
DLCO percent predicted† 3.74 (1.96, 7.14) <0.001 1.67 (1.16, 2.44) 0.005
Pulmonary hypertension** 2.65 (0.93, 7.58) 0.069 1.26 (0.32, 5.04) 0.74
Ever having had a TTE†† 1.56 (0.48, 5.10) 0.46 1.49 (0.40, 5.61) 0.55
Years from RA to ILD Dx* 1.35 (0.74, 2.46) 0.32 1.14 (0.56, 2.34) 0.72
FVC rate of change*** 3.42 (1.61, 7.24) 0.001
DLCO rate of change*** 1.72 (1.07, 2.74) 0.024