Key-words:
Interstitial lung disease - Libya - systemic sclerosis
Introduction
Systemic sclerosis (SSc) is a multisystem connective tissue disease with unknown etiology,
characterized by aberrant immune activation, endothelial dysfunction, vascular injury,
and fibroblast dysfunction with resultant excessive collagen production and fibrosis
of the skin and various internal organs.[[1]],[[2]]
Pulmonary involvement, such as interstitial lung disease (ILD) and pulmonary hypertension
(PH), accounts for significant morbidity and is the leading cause of SSc-related morbidity
and mortality.[[3]],[[4]] The exact prevalence of ILD in SSc is difficult to estimate because the patient
is clinically asymptomatic early in the course.[[5]] It has been detected in 50%–60% of SSc patients by high-resolution computed tomography
(HRCT).[[6]] The risk factors for the development of SSc-ILD include diffuse cutaneous systemic
sclerosis (dcSSc),[[7]] shorter disease duration,[[8]] older age at disease onset, and the presence of anti-topoisomerase I antibody and/or
the absence of anticentromer antibody (ACA).[[7]] ILD typically occurs early in the course of dcSSc, especially within 3 years after
the onset of disease,[[7]],[[8]] whereas ILD occurs at any time of disease course in limited cutaneous systemic
sclerosis (lcSSc) patients.[[9]] The clinical course of SSc-ILD is variable; some patients show stability in forced
vital capacity (FVC), while others show a progressive decline in lung function.[[10]] ILD mostly progresses within 4 years after the onset of SSc, and afterward, the
progression becomes slow or stops completely, even without any treatment.[[11]] It is reported that severe ILD, showing a decline in FVC below 50%, constitutes
around 15% of total SSc.[[12]]
The aim of the current study was to investigate the characteristics and clinical manifestations
of ILDs with SSc in eastern part of Libya.
Patients and Methods
Of all patients attending different rheumatology clinics in eastern part of Libya
between January 2018 and September 2020, forty patients (36 females and 4 males) were
included in this study. The selected patients were diagnosed as having SSc and fulfilled
the American College of Rheumatology/European League Against Rheumatism 2013 revised
classification criteria of having either a dcSSc or lcSSc disease subset for SSc.[[13]] Patients with other collagen vascular diseases/mixed connective tissue disorders
and overlap syndromes were excluded.
After obtaining informed consent, basic demographic details were collected, including
age, gender, disease duration at the time of presentation, detailed history, and clinical
examination. Autoimmune profiling included rheumatoid factor, antinuclear antibodies
(ANAs), and autoantibodies against topoisomerase I (anti-Scl-70 antibodies) immunofluorescence
in all the patients and its various patterns were noted.
Pulmonary function test (PFT) was performed according to the American Thoracic Society
guidelines.[[14]] Restrictive lung disease was diagnosed if the percentage of predicted FVC was <80%.[[15]] Obstructive lung disease was diagnosed if the forced expiratory volume at 1 s/FVC
was <70%. All patients underwent a chest radiograph, and HRCT was performed when indicated.
Pulmonary involvement was defined as either pulmonary fibrosis (bilateral reticular
nodular on chest X-ray [CXR], interstitial pneumonitis/ground-glass opacities/fibrosis
on HRCT) or FVC <70% of predicted.[[16]]
Data were analyzed using the Statistical Package for the Social Sciences (SPSS) 17.0
(SPSS Inc., Chicago, IL, USA). Descriptive statistics of the different variables were
presented as frequencies and percentages or as means ± standard deviation. For statistical
comparisons, independent samples Chisquare test was employed for testing statistical
significance of association between two discrete variables. Significant value is set
up at P<0.05.
Results
Patients data
The baseline characteristics of the study participants are shown in [[Table 1]]. The male: female ratio was 1:9 with a mean age at diagnosis 37.5 ± 9.6 years and
duration of illness 6 ± 4 years. Diffuse SSc was seen in 62.5% of the patients with
the rest diagnosed with limited SSc. Using the New York Heart Association function
test, 75% of patients suffered from dyspnea of different intensity and 37% suffered
from dry cough. The respiratory symptoms leading to diagnosis of ILD were apparent
in 45% of patients [[Table 1]].
Table 1: Demographic characteristics of the studied participants
Common presenting complaints and comorbidities
The most common presenting complaints included gastrointestinal reflux (GIR) in 72.5%,
digitalis ulcerations in 40%, and synovitis/arthritis (diffuse 40% and limited 25%)
of all patients. Other comorbidities included congestive heart failure in 12.5%, PH
in 15%, and renal impairments in 7.5% of all patients [[Table 2]].
Table 2: Common presenting complaints of the studied participants
Systemic findings
Among systemic findings, 31 participants (77.5%) had bilateral crepitation and 23
(57.5%) participants had loud P2. Among the forty participants with ILD, all of them
had skin thickening and Raynaud's phenomenon [results are not shown in a table].
Blood investigations
Blood investigations are given in [[Table 3]]. Thirty-seven and a half percent of the participants had hemoglobin <10 g/dL. Erythrocyte
sedimentation rate of more than 30 mm/h was seen in 52.5%, and 10% of participants
had creatinine blood levels of more than 1.2 mg/dL. ANAs were present in 15% of the
participants. On analysis of the immunoblotting for ANAs, anti-Scl-70 was the most
common and seen in 45%, followed by anti-centromere Ab (25%), anti-U1 RNP (5%), and
anti-U3 RNP in 10% of the participants [[Table 3]].
Table 3: Blood investigations of the studied participants
Diagnostic tests
Among radiological features, 72.5% of the participants had reticulonodular shadows
on CXR [[Table 4]]. PFT showed that 45% of all participants had FVC <70%. Among forty participants,
HRCT showed ground-glass appearance in 20% of the patients; honeycombing was the predominant
finding in 37.5%, followed by traction bronchiectasis seen in 20% of the participants.
regarding echocardiographic findings, 12.5% of the patients found to have cardiomyopathy,
15% have signs of PH which was confirmed in 10% of them by right-sided cardiac catheterization.
Table 4: Diagnostic tests done for the studied participants
Statistically, the duration of the disease, dyspnea, dry cough, GIR, bilateral crepitation,
and reticulonodular shadow in CXR were all significantly associated with extensive
ILD with FVC <70 (P<0.05). Other factors, such as anti-Scl-70 positivity and abnormal
ECHO, were not significantly associated with pulmonary involvement (P > 0.05).
Treatments given to patients
The results of treatments given to the patients are not shown in a table. The treatments
started in all patients with low doses of oral steroids (10 mg or less). Two patients
(5%) received mycophenolate 2 g daily. Sixteen patients (40%) received cyclophosphamide
1 g monthly for 6 months. Two patients (5%) received methotrexate up to 12 mg weekly.
Comparing response to treatment among our patients 6 months later, we found a partial
response with improvement of PFT and stationary disease progression on serial HRCT
scan among those who received cyclophosphamide. No deterioration of PFT was reported
among the one patient who received methotrexate, or the two patients who received
mycophenolate.
Unfortunately, five patients (12.5%) died during the study period: two of them (5%)
were complicated by PH and renal crises, two (5%) have severe cardiomyopathy, and
one (2.5%) has severe lung disease with renal impairment.
Discussion
Few publications reported findings specific to the SSc-ILD population.[[17]] ILD was estimated to affect ~35% of the SSc patients in Europe and ~52% in North
America; however, the method of ILD assessment may potentially contribute to differences
in the observed frequencies. For example, when diagnosed through HRCT, ILD was estimated
to affect 32.3%–47.0% of the SSc patients in Europe, whereas only 18.8% of the patients
were reported to be affected when diagnosed based on reduced lung function.[[18]] According to the European Scleroderma Trials and Research group, ILD was reported
to affect 53% of the cases with dcSSc and 35% of the cases with lcSSc.[[19]]
The mean age at diagnosis of SSc-ILD patients in the present study (37.5 ± 9.6 years)
was comparatively similar to patients reported from Egypt (40.6 ± 12.5)[[20]] and slightly lower than the mean age of patients reported in the UK (46 ± 11 years)
over the period of 1985–2001[[21]] and (61.8 ± 11.1) from 2000 to 2009.[[22]] Another study from the USA in the period from 1997 to 2013 reported a mean age
at diagnosis of SSc-ILD of (54.5 ± 13.2 years).[[23]] Similarly, the Pulmonary Hypertension Assessment and Recognition of Outcomes in
Scleroderma (PHAROS) registry in the United States and Canada estimated the median
age of SSc-ILD patients to be 52.5 years.[[24]]
As for many autoimmune diseases,[[25]] most patients with SSc-ILD are female. Our current study revealed that SSc-ILD
is predominantly more frequent among females, with a male: female ratio of 1:9. Same
results were reported by an Egyptian study with male to female ratio of 1:14[[20]] another UK cohort study which was conducted over the period of 2000-2009 reported
a female predominance of pulmonary involvement among SSc patients.[[22]] PHAROS registry also found predominant female gender of 78%[[24]] and accounting for 89% of SSc-ILD patients who had undergone HRCT in a cross-sectional
study conducted in Canada.[[22]]
In the current study, 32 patients (80%) have evidence of ILD by HRCT of the chest;
this was consistent with Hafez et al.[[20]] and Solomon et al.[[26]] The most common patterns in the HRCT in the current study were honeycombing followed
by ground-glass opacity, traction bronchiectasis, and reticulonodular shadowing. Compared
with other studies done,[[19]],[[20]] ground-glass opacity was the most frequent finding on HRCT, followed by septal
thickening, honeycombing, bronchiectasis, and consolidations.
In the current study, PH was reported among 15% of patients; a higher prevalence was
reported by other studies,[[20]],[[21]],[[26]],[[27]] who reported PH in 13%–35% of patients. Furthermore, Hachulla et al.[[28]] showed that 55% of patients had PH. This difference could be due to dependence
on transthoracic ECHO assessment, with no further evaluation by right-sided heart
catheterization.
As expected, ILD was more prevalent among patients with dcSSc compared with those
with lcSSc (62.5% and 37.5%, respectively). This is consistent with other reported
studies.[[19]],[[20]],[[29]]
The most frequently used therapy was cyclophosphamide 1 g monthly for 6 months; we
found a partial response with improvement of PFT and stationary disease progression
on serial HRCT. Becker et al. described a high SSc-ILD response rate assessed by FVC and diffusing capacity for
carbon monoxide (DLCO) in patients with low FVC values before cyclophosphamide therapy.[[30]] On the other hand, two meta-analyses failed to show a significant benefit of cyclophosphamide
on SSc-ILD lung functions.[[31]] The same results were reported by Adler et al.,[[32]] in which analysis of using cyclophosphamide alone or in combination with steroids
did not result in differences in the slope of DLCO or FVC values compared to all other
patients.
In this study, a significant association was found between severity of ILD and patients
with gastroesophageal reflux disease (GERD), longer duration of disease, dyspnea,
cough, bilateral crepts, and CXR. The same results were reported by Hafez et al.[[20]] who reported that longer disease duration is associated with increased risk of
both ILD and PH, dry cough, crepitations, and dyspnea. The association between ILD
and GERD is well documented in a recent study.[[33]]
Conclusion
ILD is a serious complication of SS; it is more common among patients with dcSS. Chest
HRCT is very sensitive to detect ILD. In this study, a significant association was
found between severity of ILD and patients with GERD, longer duration of the disease,
dyspnea, cough, bilateral crepts, and CXR.
