Methods
Computer based medical records of our ILD cohort were investigated. ILD
diagnosis was confirmed by evaluation of high resolution computed
tomography (HRCT) images. Diagnoses of CTDs (SSc, RA, pSS, DM/PM, IPAF)
were made with their corresponding classification criteria [14-18].
Demographic features, smoking history, type of symptoms, time at onset
of respiratory symptoms, time at diagnosis, laboratory results,
serologic tests including anti-nucleolar antibodies, extractable nuclear
antigen (ENA) panel, rheumatoid factor, anti-citrullinated peptide and
anti-neutrophil cytoplasmic antibodies were recorded.
Our ILD cohort was established in 2010 jointly by members from
rheumatology and pulmonary departments. Since then, team members meet
weekly to evaluate CTD-ILD patients (including symptoms, physiologic
tests and imaging studies) and make decisions for individual treatment
plans. Functional assessment of patients were performed by Modified
Medical Research Council (MMRC)[19]. Pulmonary function tests (PFTs)
were performed at baseline and every 6-months periods thereafter
including; forced expiratory volume in 1 min (FEV1), forced vital
capacity (FVC), and DLCO, expressed as percentages of predicted values
adjusted fora ge, sex, height and hemoglobin level, according to
techniques accepted by the American Thoracic Society (ATS)[20]. HRCT
was performed at baseline then annually, or in case of a new significant
respiratory symptom that suggest acute exacerbation of lung disease or
significant deterioration of physiological parameters. ILD patterns were
classified as non-specific interstitial pneumonia (NSIP), usual
interstitial pneumonia (UIP) according to HRCT findings including ground
glass opacities, traction bronchiectasis and sub-pleural honeycombing.
Pulmonary involvement in HRCT in SSc patients was graded as limited or
extended based on extent of reticular pattern, as suggested per
consensus of experts[21]. In this consensus report, experts suggest
to evaluate HRCT at 5 different levels for total disease extent of
reticulation, for other rheumatologic disease ILD disease there is not
any other radiological scoring system , thus same scoring system was
applied for those sub-types. Modified Gender-Age-Physiology [22]
index was used for prognosis [23].
Medications used, including systemic corticosteroids, synthetic and
biologic disease-modifying anti-rheumatic drugs (DMARD), AZA, CYC and
were meticulously reviewed. There was not any other immunsuppresive
drugs for the treatment of ILD during the induction therapy, which took
six months. Clinically significant side effects were
nausea/vomiting/abdominal pain impairing oral intake, increased liver
function tests≥3 timesof upper limit of normal, neutrophil count
of<1500/mm3, thrombocyte count
<150,000/mm3, and hemorrhagic cystitis.
Primary outcome measure was treatment response at six-month after
introduction of induction therapy. Radiological progression was defined
as , more than 10% increase in reticular pattern on HRCT, functional
progression defined as worsening in FVC greater than 10% or DLCO
greater than 15%and clinical progression defined as increase in MMRC
score. The patients had to have detoration in at least two of these
domains in order to have progressive disease.
Categorical variables were given as numbers and percentages. Continuous
data were as mean ± standard deviation (SD) or median (interquartile
range). Conformity of continuous variables to normal distribution was
evaluated using visual (histogram and probability graphs) and analytical
methods (Kolmogorov-Smirnov / Shapiro-Wilk tests). If variables were
normally distributed Student t-test was used, if not, Mann Whitney U
test was used for comparison. Comparison of categorical variables was
made with Chi-square or Fisher’s exact tests. A p-value of 0.05 or less
was considered as statistically significant in all analyzes. Propensity
score was used to explain the differences of patient groups receiving
AZA and CYC. The propensity score value for each patient was calculated
using a logistic regression model containing the determined variables.
Two to one (One to two (1: 2)) nearest-neighbor matching and caliper
width of 0.2 (caliper width of 0.2) were performed.