Abstracts
OBJECTIVE:
To describe the characteristics of a cohort of patients with lung-dominant connective tissue disease (LD-CTD).
METHODS:
This was a retrospective study of patients with interstitial lung disease (ILD), positive antinuclear antibody (ANA) results (≥ 1/320), with or without specific autoantibodies, and at least one clinical feature suggestive of connective tissue disease (CTD).
RESULTS:
Of the 1,998 patients screened, 52 initially met the criteria for a diagnosis of LD-CTD: 37% were male; the mean age at diagnosis was 56 years; and the median follow-up period was 48 months. During follow-up, 8 patients met the criteria for a definitive diagnosis of a CTD. The remaining 44 patients comprised the LD-CTD group, in which the most prevalent extrathoracic features were arthralgia, gastroesophageal reflux disease, and Raynaud's phenomenon. The most prevalent autoantibodies in this group were ANA (89%) and anti-SSA (anti-Ro, 27%). The mean baseline and final FVC was 69.5% and 74.0% of the predicted values, respectively (p > 0.05). Nonspecific interstitial pneumonia and usual interstitial pneumonia patterns were found in 45% and 9% of HRCT scans, respectively; 36% of the scans were unclassifiable. A similar prevalence was noted in histological samples. Diffuse esophageal dilatation was identified in 52% of HRCT scans. Nailfold capillaroscopy was performed in 22 patients; 17 showed a scleroderma pattern.
CONCLUSIONS:
In our LD-CTD group, there was predominance of females and the patients showed mild spirometric abnormalities at diagnosis, with differing underlying ILD patterns that were mostly unclassifiable on HRCT and by histology. We found functional stability on follow-up. Esophageal dilatation on HRCT and scleroderma pattern on nailfold capillaroscopy were frequent findings and might come to serve as diagnostic criteria.
Idiopathic interstitial pneumonias; Autoantibodies; Connective tissue diseases; Autoimmunity
OBJETIVO:
Descrever as características de uma coorte de pacientes com colagenose pulmão dominante (CPD).
MÉTODOS:
Estudo retrospectivo de pacientes com doença pulmonar intersticial (DPI), anticorpo antinuclear (ANA) positivo (≥ 1/320), com ou sem autoanticorpos específicos, e com a presença de ao menos uma manifestação clínica sugestiva de doença do tecido conjuntivo (DTC).
RESULTADOS:
Dos 1.998 avaliados, 52 preencheram inicialmente os critérios para o diagnóstico de CPD: 37% eram homens; a média de idade ao diagnóstico era de 56 anos e a mediana do tempo de seguimento era de 48 meses. Durante o seguimento, 8 pacientes preencheram os critérios para um diagnóstico definitivo de DTC. Os 44 pacientes restantes formaram o grupo CPD, no qual as manifestações extratorácicas mais prevalentes foram artralgia, doença do refluxo gastroesofágico e fenômeno de Raynaud. Os autoanticorpos mais prevalentes nesse grupo foram ANA (89%) e anti-SSA (anti-Ro, 27%). A média de CVF no início e na última avaliação foi de 69,5% e 74,0% do predito, respectivamente (p > 0,05). Pneumonia intersticial não específica e pneumonia intersticial usual foram identificadas em 45% e 9% das TCARs, respectivamente; 36% das TCARs eram não classificáveis. Uma prevalência semelhante foi identificada na histologia. Dilatação esofágica difusa foi identificada em 52% das TCARs. Capilaroscopia subungueal foi realizada em 22 pacientes; 17 apresentavam um padrão de esclerodermia.
CONCLUSÕES:
No grupo CPD, houve predominância feminina, e os pacientes apresentaram alterações espirométricas leves ao diagnóstico, com diferentes padrões de DPI, em sua maioria não classificáveis, tanto em TCAR como na histologia. Estabilidade funcional foi identificada no seguimento. A dilatação esofágica em TCAR e o padrão de esclerodermia na capilaroscopia subungueal foram achados frequentes que poderiam servir como critérios diagnósticos.
Pneumonias intersticiais idiopáticas; Autoanticorpos; Doenças do tecido conjuntivo; Autoimunidade
Introduction
There is a dilemma surrounding the classification of patients with interstitial lung
diseases (ILDs) and clinical features that are suggestive of formes
frustes (limited forms) of connective tissue disease (CTD), because such
patients do not meet the accepted rheumatological criteria for a definitive diagnosis of
CTD.(
11 Pereira DA, Kawassaki Ade M, Baldi BG. Interpretation of autoantibody
positivity in interstitial lung disease and lung-dominant connective tissue disease.
J Bras Pneumol. 2013;39(6):728-41.
http://dx.doi.org/10.1590/S1806-37132013...
2 Katzenstein AL, Fiorelli RF. Nonspecific interstitial
pneumonia/fibrosis. Histologic features and clinical significance. Am J Surg Pathol.
1994;18(2):136-47.
http://dx.doi.org/10.1097/00000478-19940...
-
33 Travis WD, Hunninghake G, King TE Jr, Lynch DA, Colby TV, Galvin JR, et
al. Idiopathic nonspecific interstitial pneumonia: report of an American Thoracic
Society Project. Am J Respir Crit Care Med. 2008;177(12):1338-47.
http://dx.doi.org/10.1164/rccm.200611-16...
) Since the first recognition of the nonspecific interstitial pneumonia
(NSIP) pattern as a possible independent disease, it has been strongly associated with
CTD.(
44 Fischer A, West SG, Swigris JJ, Brown KK, du Bois RM. Connective tissue
disease-associated interstitial lung disease: a call for clarification. Chest.
2010;138(2):251-6.
http://dx.doi.org/10.1378/chest.10-0194...
) Previous studies have shown different characteristics regarding the
prognosis and natural history of idiopathic interstitial pneumonia (IIP) with a
"rheumatological flavor" but without a definitive diagnosis of CTD.(
55 Kinder BW, Collard HR, Koth L, Daikh DI, Wolters PJ, Elicker B, et al.
Idiopathic nonspecific interstitial pneumonia: lung manifestation of undifferentiated
connective tissue disease? Am J Respir Crit Care Med.
2007;176(7):691-7.
http://dx.doi.org/10.1164/rccm.200702-22...
6 Vij R, Noth I, Strek ME. Autoimmune-featured interstitial lung disease:
a distinct entity. Chest. 2011;140(5):1292-9.
http://dx.doi.org/10.1378/chest.10-2662...
-
77 Corte TJ, Copley SJ, Desai SR, Zappala CJ, Hansell DM, Nicholson AG, et
al. Significance of connective tissue disease features in idiopathic interstitial
pneumonia. Eur Respir J. 2012;39(3):661-8.
http://dx.doi.org/10.1183/09031936.00174...
) The majority of such studies have departed from the NSIP histology to
scrutinize the clinical, physiological, and tomographic features of patients. However,
it remains unclear whether other ILD patterns are associated with this subgroup, and
only a few studies have considered patterns that are either exclusively usual
interstitial pneumonia (UIP)(
88 Lee JS, Kim EJ, Lynch KL, Elicker B, Ryerson CJ, Katsumoto TR, et al.
Prevalence and clinical significance of circulating autoantibodies in idiopathic
pulmonary fibrosis. Respir Med. 2013;107(2):249-55.
http://dx.doi.org/10.1016/j.rmed.2012.10...
,
99 Alhamad EH, Al-Kassimi FA, Alboukai AA, Raddaoui E, Al-Hajjaj MS, Hajjar
W, et al. Comparison of three groups of patients with usual interstitial pneumonia.
Respir Med. 2012;106(11):1575-85.
http://dx.doi.org/10.1016/j.rmed.2012.07...
) or mixed.(
66 Vij R, Noth I, Strek ME. Autoimmune-featured interstitial lung disease:
a distinct entity. Chest. 2011;140(5):1292-9.
http://dx.doi.org/10.1378/chest.10-2662...
,
1010 Mittoo S, Gelber AC, Christopher-Stine L, Horton MR, Lechtzin N, Danoff
SK. Ascertainment of collagen vascular disease in patients presenting with
interstitial lung disease. Respir Med. 2009;103(8):1152-8.
http://dx.doi.org/10.1016/j.rmed.2009.02...
) Although patients with CTD and ILD have better survival, regardless of
their histology,(
1111 Park JH, Kim DS, Park IN, Jang SJ, Kitaichi M, Nicholson AG, et al.
Prognosis of fibrotic interstitial pneumonia: idiopathic versus collagen vascular
disease-related subtypes. Am J Respir Crit Care Med.
2007;175(7):705-11.
http://dx.doi.org/10.1164/rccm.200607-91...
12 Flaherty KR, Colby TV, Travis WD, Toews GB, Mumford J, Murray S, et al.
Fibroblastic foci in usual interstitial pneumonia: idiopathic versus collagen
vascular disease. Am J Respir Crit Care Med. 2003;167(10):1410-5.
http://dx.doi.org/10.1164/rccm.200204-37...
-
1313 Kairalla RA. Interstitial lung disease in scleroderma. J Bras Pneumol.
2005;31(4):1-3.
) uncertainties remain regarding how isolated autoantibody positivity in IIP
affects the natural course of the disease and the response to treatment.(
77 Corte TJ, Copley SJ, Desai SR, Zappala CJ, Hansell DM, Nicholson AG, et
al. Significance of connective tissue disease features in idiopathic interstitial
pneumonia. Eur Respir J. 2012;39(3):661-8.
http://dx.doi.org/10.1183/09031936.00174...
,
1414 Fischer A, Pfalzgraf FJ, Feghali-Bostwick CA, Wright TM, Curran-Everett
D, West SG, et al. Anti-th/to-positivity in a cohort of patients with idiopathic
pulmonary fibrosis. J Rheumatol. 2006;33(8):1600-5.
)
Fischer et al.(
44 Fischer A, West SG, Swigris JJ, Brown KK, du Bois RM. Connective tissue
disease-associated interstitial lung disease: a call for clarification. Chest.
2010;138(2):251-6.
http://dx.doi.org/10.1378/chest.10-0194...
) recently proposed "lung-dominant" CTD, or LD-CTD, as a new classification
and the term best suited to describing the association between ILD and undifferentiated
CTD, theretofore referred to by myriad terms. The authors proposed comprehensive and
restrictive provisional criteria that recognize any classical ILD pattern as a possible
association with LD-CTD. Positivity for autoantibodies that are more specific, with
special attention to their titers, and histological features that are strongly
associated with collagen vascular diseases were also included in the definition of
LD-CTD proposed by the authors.(
44 Fischer A, West SG, Swigris JJ, Brown KK, du Bois RM. Connective tissue
disease-associated interstitial lung disease: a call for clarification. Chest.
2010;138(2):251-6.
http://dx.doi.org/10.1378/chest.10-0194...
)
We hypothesized that comprehensive and restrictive criteria would be needed in order to define LD-CTD appropriately. We further hypothesized that the definition would be more accurate if ILDs were accompanied not only by autoantibody positivity but also by any extrathoracic feature of CTD. The main objective of this study was to characterize a retrospective cohort of patients in Brazil who met the clinical, functional, serological, tomographic, and histological criteria for a diagnosis of LD-CTD, including the presence of extrathoracic manifestations. We also evaluated how the pulmonary physiology behaves throughout follow-up in patients with LD-CTD.
Methods
Patients
This was a retrospective study of patients with ILD seen at the outpatient clinic of
a tertiary university hospital in Brazil over the previous 16 years (1996-2012). From
among the 1,998 cases in the ILD patient database, we selected 75 in which the
patients met the LD-CTD criteria proposed by Fischer et al.,(
44 Fischer A, West SG, Swigris JJ, Brown KK, du Bois RM. Connective tissue
disease-associated interstitial lung disease: a call for clarification. Chest.
2010;138(2):251-6.
http://dx.doi.org/10.1378/chest.10-0194...
) as detailed in Chart 1, at the
time of their first clinical evaluation. After the records had been evaluated by a
multidisciplinary team composed of radiologists, pathologists, and pulmonologists
with expertise in the diagnosis of ILD, we excluded patients with classifiable forms
of CTD or ILDs with known etiologies, such as hypersensitivity pneumonitis, smoking,
and idiopathic pulmonary fibrosis (IPF). In addition, we excluded cases in which
basic initial complementary tests were not performed. A rheumatologist also evaluated
every case included in the analysis.
Data collection
On the basis of our review of the patient charts, we selected ILD patients with a high antinuclear antibody (ANA) titer (≥ 1:320), with or without positivity for specific autoantibodies, and at least one clinical extrathoracic feature suggestive of CTD. We collected data related to demographic characteristics; comorbidities; clinical features of CTD (including clinical extrathoracic features at diagnosis and over the course of the disease); imaging findings (HRCT scans of the chest and nailfold capillaroscopy); pulmonary function tests (PFTs) at the initial visit and last available evaluation; biological parameters (including the results of a broad autoantibody panel and routine blood tests); histological features; and details of the medical treatment.
Within the data collected at the initial evaluation, we searched for extrathoracic features suggestive of CTD, including arthritis; arthralgia; morning stiffness; photosensitivity; cutaneous lesions, such as "mechanic's hands" (hyperkeratosis of the hands or fingers), Gottron's papules, and heliotrope rash; Raynaud's phenomenon; sicca syndrome (dry mouth, dry eyes, or a positive Schirmer's test result); and refractory gastrointestinal symptoms, such as heartburn, acid regurgitation, and dysphagia.
We collected initial and last-registered FVC and FEV1 values. We used
standard spirometry techniques, and the predicted spirometric values were derived
from the data reported for the Brazilian population.(
1515 Pereira CA, Sato T, Rodrigues SC. New reference values for forced
spirometry in white adults in Brazil. J Bras Pneumol.
2007;33(4):397-406.
http://dx.doi.org/10.1590/S1806-37132007...
) The chest HRCT scan patterns were retrieved from radiology reports made
by radiologists experienced in evaluating ILD and were based on international
consensus criteria.(
1616 American Thoracic Society; European Respiratory Society. American
Thoracic Society/European Respiratory Society International Multidisciplinary
Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint
statement of the American Thoracic Society (ATS), and the European Respiratory
Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS
Executive Committee, June 2001. Am J Respir Crit Care Med.
2002;165(2):277-304.
http://dx.doi.org/10.1164/ajrccm.165.2.a...
17 Travis WD, Costabel U, Hansell DM, King TE Jr, Lynch DA, Nicholson AG,
et al. An official American Thoracic Society/European Respiratory Society statement:
update of the international multidisciplinary classification of the idiopathic
interstitial pneumonias. Am J Respir Crit Care Med.
2013;188(6):733-48.
http://dx.doi.org/10.1164/rccm.201308-14...
-
1818 Baldi BG, Pereira CA, Rubin AS, Santana AN, Costa AN, Carvalho CR, et
al. Highlights of the Brazilian Thoracic Association guidelines for interstitial lung
diseases. J Bras Pneumol. 2012;38(3):282-91.
http://dx.doi.org/10.1590/S1806-37132012...
) To standardize the HRCT criteria for esophageal dilatation on HRCT
images, two experienced pulmonologists blindly evaluated HRCT scans for the presence
of esophageal dilatation, occurring below the aortic arch with a large (> 10-mm)
collection of intraluminal air in the coronal plane on four or more consecutive axial
images.(
1919 Silva CI, Marchiori E, Souza Júnior AS, Müller NL; Comissão de Imagem da
Sociedade Brasileira de Pneumologia e Tisiologia. Illustrated Brazilian consensus of
terms and fundamental patterns in chest CT scans. J Bras Pneumol.
2010;36(1):99-123.
http://dx.doi.org/10.1590/S1806-37132010...
) The esophagus was also considered dilated when it was filled with fluid
or showed an air-fluid level.(
2020 Fagundes MN, Caleiro MT, Navarro-Rodriguez T, Baldi BG, Kavakama J,
Salge JM, et al. Esophageal involvement and interstitial lung disease in mixed
connective tissue disease. Respir Med. 2009;103(6):854-60.
http://dx.doi.org/10.1016/j.rmed.2008.12...
) The autoantibody panel consisted of the following tests: ANA (titer and
pattern), rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP),
anti-Ro, anti-La, anti-ribonucleoprotein (anti-RNP), anti-topoisomerase I
(anti-Scl-70), anticentromere, anti-Jo-1, anti-DNA, and anti-Smith (anti-Sm).
Histological patterns were also retrieved from anatomopathological reports made by
experienced lung pathologists and based on international consensus
statements.(
1616 American Thoracic Society; European Respiratory Society. American
Thoracic Society/European Respiratory Society International Multidisciplinary
Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint
statement of the American Thoracic Society (ATS), and the European Respiratory
Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS
Executive Committee, June 2001. Am J Respir Crit Care Med.
2002;165(2):277-304.
http://dx.doi.org/10.1164/ajrccm.165.2.a...
,
1717 Travis WD, Costabel U, Hansell DM, King TE Jr, Lynch DA, Nicholson AG,
et al. An official American Thoracic Society/European Respiratory Society statement:
update of the international multidisciplinary classification of the idiopathic
interstitial pneumonias. Am J Respir Crit Care Med.
2013;188(6):733-48.
http://dx.doi.org/10.1164/rccm.201308-14...
)
Statistical analysis
Descriptive statistics were obtained with the statistical software STATA, version 12.1 (StataCorp LP, College Station, TX, USA). Categorical variables are expressed as proportions, and continuous variables are expressed as median (interquartile range [IQR]) or mean ± standard deviation. Statistical measurements were performed with the Student's t-test, or Wilcoxon rank sum (Mann-Whitney U) test, for continuous variables, and with Fisher's exact test for categorical variables. To evaluate the associations between two continuous variables, we used multiple linear regression, adjusting for covariates according to model-building strategies. Multiple test correction (Bonferroni correction) was performed for parametric tests. We managed missing data (all missing completely at random) using complete case analysis. The level of statistical significance was set at p < 0.05.
Results
Of the 75 patients selected, 23 were excluded from the analysis because the spirometric data were incomplete. Therefore, there were 52 patients who met the LD-CTD criteria at baseline (Table 1). Approximately half (28 patients) had a history of smoking, and 21 reported relevant environmental exposure, mainly to mold (13 patients), which was, however, not consistent enough to yield a diagnosis of hypersensitivity pneumonitis. By the end of follow-up-after a median of 61 months (IQR, 48.5-78.0 months)-only 8 patients met the criteria for a definitive diagnosis of a CTD (definite-CTD group): antisynthetase syndrome (n = 3); systemic sclerosis (n = 2); Sjögren's syndrome (n = 2); and rheumatoid arthritis (n = 1). Compared with those who did not meet the criteria for another definitive diagnosis (i.e., the LD-CTD patients), the patients in the definite-CTD group had longer follow-up periods and worse PFT results at the initial evaluation, although the differences were of only marginal statistical significance (Tables 1 and 2). Among the definite-CTD group patients, the histology samples showed only unclassifiable patterns. However, four of those patients underwent transbronchial biopsy. The definite-CTD and LD-CTD groups did not differ statistically in terms of any other characteristics, whether related to the autoantibody profiles or to the extrathoracic features of CTD.
In the LD-CTD group (n = 44), there was a predominance of females and the median follow-up period was 30 months (IQR, 16-68 months), as shown in Table 1. The shortest follow-up period was 6 months and the longest was 120 months. As can also be seen in Table 1, the most prevalent extrathoracic features were arthralgia and symptoms of gastroesophageal reflux disease (GERD), both in approximately two-thirds of the group, followed by Raynaud's phenomenon, in 14 patients (32%); cutaneous lesions, in 13 patients (30%); and proximal muscle weakness, in 11 patients (25%).
We found that, in the LD-CTD group, the most prevalent autoantibody was ANA, which was identified in 39 patients, with a median titer of 1:320 (IQR, 1:160-1:640), followed by anti-Ro, in 12 patients, and RF, in 10 (Table 1). However, we did not classify these patients as having LD-CTD solely on the basis of ANA positivity. A diagnosis of LD-CTD can be made on the basis of a high titer for any autoantibody. Therefore, some patients were included in the LD-CTD group because they had a high titer for a specific autoantibody despite showing a low ANA titer. A high ANA titer (≥ 1:320) was identified in 22 of the 39 ANA-positive patients, and the remaining 17 ANA-positive patients were included in the LD-CTD group on the basis of high titers for anti-Ro (5 patients), RF (4 patients), anti-Sm (3 patients), anti-Jo-1 (2 patients), anti-La (2 patients), or anti-DNA (1 patient).
Nailfold capillaroscopy was initially performed in 22 patients, two of whom later received a definitive diagnosis of a CTD. Both had a scleroderma pattern of capillary changes and eventually met the criteria for systemic sclerosis. In the LD-CTD group, capillaroscopic abnormalities were identified in 15 patients, a scleroderma pattern being seen in 11 (Table 1).
At diagnosis, the PFT results for the LD-CTD group patients showed mild restriction, as evidenced by low mean FVC-as a percentage of the predicted value (FVC%, 69.5% ± 21.0%) or as an absolute value (2.18 ± 0.76 L)-with no obstructive pattern (Table 2). After a median follow-up period of 30 months (IQR, 15-57 months), there were no clinically or statistically significant changes in the mean FVC (74% ± 22%; 2.19 ± 0.77 L). As can be seen in Figure 1, multiple linear regression analysis comparing the initial and final FVC% revealed that, even after adjustments for age, gender, treatment, interval between measures, and ANA titer, the initial values were the main predictors of final values (r2 = 0.75; p < 0.001). Subjects who met the criteria for a definitive diagnosis of CTD tended to have worse physiology at initial evaluation, although the difference was of only marginal statistical significance (Table 2).
Multiple linear regression analysis between initial and final FVC as a percentage of the predicted value (FVC%) in patients with lung-dominant connective tissue disease (n = 32), showing a strong correlation between initial and final values after adjustment for covariates (time between measures, age, gender, treatment, and antinuclear antibody titer).
First-evaluation HRCT scans of the chest were available for 42 patients. As depicted in Figure 2, the predominant patterns were ground-glass opacities (in 90%), reticulation (in 90%), and traction bronchiectasis (in 78%). Twenty-two patients showed diffuse esophageal dilatation. Peribronchovascular distribution was reported in 11 patients, even among those with deemed-definite classical HRCT patterns. The HRCT pattern was classifiable in 26 patients, NSIP and UIP patterns being noted in 19 and 4 patients, respectively. Most importantly, 36% of the initial HRCT scans were considered unclassifiable after evaluation by an experienced thoracic radiologist. Follow-up HRCT scans were available for only 33 patients, and the findings remained unchanged in 57%.
First-evaluation chest HRCT scan findings in patients with lung-dominant connective tissue disease. (A) Bar chart of the total count of HRCT findings in 42 patients. Although ground-glass opacity (GGO), reticulation, and traction bronchiectasis predominated, roughly half of the scans met the published criteria for esophageal disease.(20) (B) Pie chart of the patterns assigned by an experienced radiologist. NSIP: nonspecific interstitial pneumonia; UIP: usual interstitial pneumonia; and OP: organizing pneumonia.
Histological data were available for 26 of the LD-CTD group patients. There were 18 surgical samples and 8 transbronchial samples, evaluation of the latter being conclusive in only one patient with organizing pneumonia. An unclassifiable pattern, mainly transbronchial, was seen in 38% of the samples. The predominant pattern in the surgical samples was NSIP (in 27%), followed by UIP (in 15%) and organizing pneumonia (in 16%). Immunosuppressant therapy had been started in 44 of the LD-CTD group patients, and all of them received prednisone. The treatment regimen comprised the azathioprine/prednisone combination in 66% of the cases.
Discussion
We have reported the findings of a retrospective evaluation of a group of LD-CTD patients characterized by a predominance of young female patients who complained mainly of arthralgia and GERD symptoms, showed mild restriction on PFTs, were physiologically stable on follow-up, and predominantly had an NSIP pattern (tomographically and histologically). The most relevant autoantibodies in our sample were ANA, anti-Ro, and RF. A scleroderma pattern of capillary changes was observed in 75% of the patients who underwent nailfold capillaroscopy, and diffuse esophageal dilatation was seen on half of the HRCT scans of the chest. Both findings support the relevance of the "rheumatological flavor" in such cases. From a large population of patients diagnosed with ILD, only approximately 2.6% initially met the criteria for an LD-CTD etiology. To date, there has been no estimate of the prevalence of LD-CTD in such a population. It is of note that, after a reasonable follow-up period, 15% of those patients prospectively met the criteria for a definitive diagnosis of a CTD.
There is growing recognition that ILD might be the first or an isolated manifestation of
a CTD. (
2121 Fischer A, Brown KK. Interstitial lung disease in undifferentiated forms
of connective tissue disease. Arthritis Care Res (Hoboken).
2015;67(1):4-11.
http://dx.doi.org/10.1002/acr.22394...
) In 1995, Homma et al.,(
2222 Homma Y, Ohtsuka Y, Tanimura K, Kusaka H, Munakata M, Kawakami Y, et al.
Can interstitial pneumonia as the sole presentation of collagen vascular diseases be
differentiated from idiopathic interstitial pneumonia? Respiration.
1995;62(5):248-51.
http://dx.doi.org/10.1159/000196457...
) having followed, for up to 11 years, 68 patients in whom the initial
evaluation showed no clinical or serological evidence of CTD,(
11 Pereira DA, Kawassaki Ade M, Baldi BG. Interpretation of autoantibody
positivity in interstitial lung disease and lung-dominant connective tissue disease.
J Bras Pneumol. 2013;39(6):728-41.
http://dx.doi.org/10.1590/S1806-37132013...
) showed that it is possible for ILD to be the sole presentation of occult
CTD. Homma et al.(
2222 Homma Y, Ohtsuka Y, Tanimura K, Kusaka H, Munakata M, Kawakami Y, et al.
Can interstitial pneumonia as the sole presentation of collagen vascular diseases be
differentiated from idiopathic interstitial pneumonia? Respiration.
1995;62(5):248-51.
http://dx.doi.org/10.1159/000196457...
) showed that the incidence of definite CTD during long-term follow-up was
19%, similar to the rate observed in the present study, and also found no difference
between patients who have definite CTD and LD-CTD patients from a clinical or
serological standpoint. The authors concluded that there are no clinical markers that
are useful in predicting which patients will develop a definite CTD.
Since Homma et al.(
2222 Homma Y, Ohtsuka Y, Tanimura K, Kusaka H, Munakata M, Kawakami Y, et al.
Can interstitial pneumonia as the sole presentation of collagen vascular diseases be
differentiated from idiopathic interstitial pneumonia? Respiration.
1995;62(5):248-51.
http://dx.doi.org/10.1159/000196457...
) first suggested that ILD could be the pulmonary manifestation of an
undefined systemic autoimmune disease, the body of literature on the subject has grown
considerably. Kinder et al.(
55 Kinder BW, Collard HR, Koth L, Daikh DI, Wolters PJ, Elicker B, et al.
Idiopathic nonspecific interstitial pneumonia: lung manifestation of undifferentiated
connective tissue disease? Am J Respir Crit Care Med.
2007;176(7):691-7.
http://dx.doi.org/10.1164/rccm.200702-22...
) sought to determine whether idiopathic NSIP is actually the pulmonary
manifestation of a systemic autoimmune disease and, consequently, the respiratory
counterpart of what rheumatologists know as undifferentiated CTD (UCTD).(
2323 Mosca M, Tavoni A, Neri R, Bencivelli W, Bombardieri S. Undifferentiated
connective tissue diseases: the clinical and serological profiles of 91 patients
followed for at least 1 year. Lupus. 1998;7(2):95-100.
http://dx.doi.org/10.1191/09612039867891...
) By applying a broader set of UCTD criteria, the authors compared UCTD
patients with IIP patients (specifically IPF patients) and concluded that such criteria
could be used in predicting NSIP.(
55 Kinder BW, Collard HR, Koth L, Daikh DI, Wolters PJ, Elicker B, et al.
Idiopathic nonspecific interstitial pneumonia: lung manifestation of undifferentiated
connective tissue disease? Am J Respir Crit Care Med.
2007;176(7):691-7.
http://dx.doi.org/10.1164/rccm.200702-22...
) These preliminary results were followed by those from several retrospective
cohort studies employing different diagnostic criteria and terminology to refer to ILD
patients with equivocal CTD features. Corte et al.(
77 Corte TJ, Copley SJ, Desai SR, Zappala CJ, Hansell DM, Nicholson AG, et
al. Significance of connective tissue disease features in idiopathic interstitial
pneumonia. Eur Respir J. 2012;39(3):661-8.
http://dx.doi.org/10.1183/09031936.00174...
) called into question the specificity of UCTD criteria in predicting NSIP
and suggested that only specific features such as Raynaud's phenomenon and a compatible
demographic profile (female < 50 years of age) could predict an NSIP pattern in such
patients. Therefore, the authors of some studies have applied inclusion criteria that
are more stringent. One such study was conducted by Vij et al.,(
66 Vij R, Noth I, Strek ME. Autoimmune-featured interstitial lung disease:
a distinct entity. Chest. 2011;140(5):1292-9.
http://dx.doi.org/10.1378/chest.10-2662...
) who thus defined an entity referred to as autoimmune-featured ILD. The
authors described a UIP-predominant group of patients, in which UIP was identified on
the basis of CT scans in 62% and histology in 81%, with characteristics similar to those
of patients with IPF (older and male) and, as in the present study, relevant prevalence
of GERD symptoms. However, their findings contrast with ours regarding ILD pattern
prevalence, because we recognize the relevance of the unclassifiable pattern to this
population. Patients with unclassifiable IIP have only recently come to be considered a
possible distinct subgroup of ILD patients. When a patient cannot be satisfactorily
classified, a diagnosis of unclassifiable IIP is suggested, which is an acknowledgment
that a final diagnosis might not be achieved after a multidisciplinary discussion.
(
1717 Travis WD, Costabel U, Hansell DM, King TE Jr, Lynch DA, Nicholson AG,
et al. An official American Thoracic Society/European Respiratory Society statement:
update of the international multidisciplinary classification of the idiopathic
interstitial pneumonias. Am J Respir Crit Care Med.
2013;188(6):733-48.
http://dx.doi.org/10.1164/rccm.201308-14...
,
2424 Ryerson CJ, Urbania TH, Richeldi L, Mooney JJ, Lee JS, Jones KD, et al.
Prevalence and prognosis of unclassifiable interstitial lung disease. Eur Respir J.
2013;42(3):750-7.
http://dx.doi.org/10.1183/09031936.00131...
) Another retrospective study predicted a 10% prevalence of unclassifiable
cases in a large ILD cohort that was characteristically heterogeneous in terms of
several clinical variables.(
2424 Ryerson CJ, Urbania TH, Richeldi L, Mooney JJ, Lee JS, Jones KD, et al.
Prevalence and prognosis of unclassifiable interstitial lung disease. Eur Respir J.
2013;42(3):750-7.
http://dx.doi.org/10.1183/09031936.00131...
) It is noteworthy that 70% of our final pathological unclassifiable patterns
were observed in transbronchial biopsy samples, which is in accordance with the findings
of Ryerson et al.,(
2424 Ryerson CJ, Urbania TH, Richeldi L, Mooney JJ, Lee JS, Jones KD, et al.
Prevalence and prognosis of unclassifiable interstitial lung disease. Eur Respir J.
2013;42(3):750-7.
http://dx.doi.org/10.1183/09031936.00131...
) who reported that 69% of the unclassifiable cases identified in their study
were attributable to biopsy samples being either insufficient or unavailable. Our
results embody recognition of the updated (2013) American Thoracic Society/European
Respiratory Society joint statement on multidisciplinary classification of ILD, which
states that unclassifiable interstitial pneumonia often proves to be related to CTD,
especially when there is an overlap of histological patterns within the same
sample.(
1717 Travis WD, Costabel U, Hansell DM, King TE Jr, Lynch DA, Nicholson AG,
et al. An official American Thoracic Society/European Respiratory Society statement:
update of the international multidisciplinary classification of the idiopathic
interstitial pneumonias. Am J Respir Crit Care Med.
2013;188(6):733-48.
http://dx.doi.org/10.1164/rccm.201308-14...
) Even though transbronchial biopsy plays an unequivocal role in the
histological classification of ILD, the limitations of transbronchial biopsy samples
should be acknowledged.(
2525 Oliveira CC, Fabro AT, Ribeiro SM, Defaveri J, Capelozzi VL, Queluz TH,
et al. Evaluation of the use of transbronchial biopsy in patients with clinical
suspicion of interstitial lung disease. J Bras Pneumol.
2011;37(2):168-75.
)
When we excluded the patients who had definite CTD, we found a strong correlation
between initial and final FVC%, suggesting that the main contributor to the final value
is the initial measurement itself (Figure 1).
After adjusting for several covariates, we found that PFTs remained stable throughout
follow-up. Despite the inconclusive role played by histological patterns and the
possibility of multiple patterns in LD-CTD patients, the stability of lung function
indicates that the disease was milder in our sample than in historical samples of
patients with IPF.(
1111 Park JH, Kim DS, Park IN, Jang SJ, Kitaichi M, Nicholson AG, et al.
Prognosis of fibrotic interstitial pneumonia: idiopathic versus collagen vascular
disease-related subtypes. Am J Respir Crit Care Med.
2007;175(7):705-11.
http://dx.doi.org/10.1164/rccm.200607-91...
) Such stability was also noted on HRCT scans of the chest: at the last
evaluation, 55% of available scans showed stable interstitial abnormalities. In contrast
with our finding of stable PFT results, Kinder et al.(
2626 Kinder BW, Shariat C, Collard HR, Koth LL, Wolters PJ, Golden JA, et al.
Undifferentiated connective tissue disease-associated interstitial lung disease:
changes in lung function. Lung. 2010;188(2):143-9.
http://dx.doi.org/10.1007/s00408-009-922...
) reported significantly greater improvement in FVC% during follow-up in
patients with UCTD than in those with IPF. However, the authors defined improvement at a
low cutoff (an absolute increase ≥ 5%), lung function remained stable in a third of
their sample, and the diagnostic criteria employed in their study differed from those
applied in our study.
Nailfold capillaroscopy is an easily implemented, noninvasive methodology for evaluating
the microvascular abnormalities commonly found in several types of CTDs, especially
systemic sclerosis, polymyositis/dermatomyositis, and mixed CTD. (
2727 De Angelis R, Grassi W, Cutolo M. A growing need for capillaroscopy in
rheumatology. Arthritis Rheum. 2009;61(3):405-10.
http://dx.doi.org/10.1002/art.24274...
) In our sample, 22 patients were submitted to nailfold capillaroscopy, of
whom 17 were found to have at least one significant microvascular abnormality,
substantiating the suspicion of CTD. The sensitivity and specificity of nailfold
capillaroscopy have yet to be evaluated. However, in the recent American College of
Rheumatology/New European League Against Rheumatism revised classification criteria for
systemic sclerosis, capillaroscopy is given only minor weight in a probability
score-notably, the same weight given to interstitial lung abnormalities. (
2828 van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A,
et al. 2013 classification criteria for systemic sclerosis: an American College of
Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum
Dis. 2013;72(11):1747-55.
http://dx.doi.org/10.1136/annrheumdis-20...
) Therefore, microvascular alterations are still under scrutiny as predictors
of definite CTD.(
2727 De Angelis R, Grassi W, Cutolo M. A growing need for capillaroscopy in
rheumatology. Arthritis Rheum. 2009;61(3):405-10.
http://dx.doi.org/10.1002/art.24274...
) We strongly recommend that, in association with close physical examination
of the hands, nailfold capillaroscopy be included in the armamentarium for the initial
evaluation of ILD patients, mainly in those under high suspicion of having CTD, with
specific autoantibody positivity, and presenting with overt lesions of the skin or
joints of the hands. Another easily identifiable characteristic suggestive of associated
systemic autoimmunity is esophageal dilatation on HRCT scans, recognizable by a large
collection of intraluminal air that is fluid-filled or has an air-fluid
level.(
2020 Fagundes MN, Caleiro MT, Navarro-Rodriguez T, Baldi BG, Kavakama J,
Salge JM, et al. Esophageal involvement and interstitial lung disease in mixed
connective tissue disease. Respir Med. 2009;103(6):854-60.
http://dx.doi.org/10.1016/j.rmed.2008.12...
) In the present study, we observed a 50% prevalence of esophageal
impairment, including hiatal hernia and esophageal dilatation, corroborating our high
frequency of GERD symptoms and suggesting that it is important to screen for esophageal
dysmotility when a CTD etiology is suspected.
Our study has certain limitations, in particular the retrospective design, which
accounted for a considerable amount of missing data-an obstacle that we overcame by
performing a complete case-analysis. In addition, the evaluation time points varied
widely among patients, reducing the external validity of our results and possibly
contributing to an overestimation of physiological stability and an underestimation of
the odds of developing a definite CTD. Follow-up was longer in the definite-CTD group
patients than in the LD-CTD group patients, and the difference was statistically
significant, albeit only marginally so (p = 0.052). Furthermore, in the majority of
patients in our sample, diffusion of carbon dioxide was not measured. However, it can be
argued that, despite the ongoing debate on the appropriateness of FVC as a surrogate
marker for disease evolution, it is a physiological measure that is frequently used as
such.(
2626 Kinder BW, Shariat C, Collard HR, Koth LL, Wolters PJ, Golden JA, et al.
Undifferentiated connective tissue disease-associated interstitial lung disease:
changes in lung function. Lung. 2010;188(2):143-9.
http://dx.doi.org/10.1007/s00408-009-922...
,
2929 Raghu G, Collard HR, Anstrom KJ, Flaherty KR, Fleming TR, King TE Jr, et
al. Idiopathic pulmonary fibrosis: clinically meaningful primary endpoints in phase 3
clinical trials. Am J Respir Crit Care Med. 2012;185(10):1044-8.
http://dx.doi.org/10.1164/rccm.201201-00...
) Although evidence of esophageal impairment was common in our sample, that
should be interpreted with caution, because our findings (which were based on imaging
and symptoms) were only suggestive of esophageal involvement (specific tests to identify
unequivocal esophageal disease were not conducted). Nevertheless, this retrospective
study was the first of its kind to include patients from Brazil, where economic status
might play a role in delaying diagnosis and healthcare access. Moreover, we used a more
stringent criterion as a starting point for cohort definition,(
44 Fischer A, West SG, Swigris JJ, Brown KK, du Bois RM. Connective tissue
disease-associated interstitial lung disease: a call for clarification. Chest.
2010;138(2):251-6.
http://dx.doi.org/10.1378/chest.10-0194...
) allowing many different classical ILD patterns to be included in the study.
To our knowledge, ours is the first study assessing the importance of evaluating
nailfold capillaries for the diagnosis of LD-CTD.
In summary, a fair number of patients with ILD might present with one or more features of a CTD without meeting the established diagnostic criteria for such. Among such patients, lung disease seems to be characteristically mild, functional stability being the main feature. Attention to the standard extrathoracic features of CTD should be accompanied by attention to less straightforward GERD symptoms, diffuse esophageal dilatation on HRCT scans, and specific capillaroscopy findings. Although much, if not all, of the current evidence related to LD-CTD relies on retrospective designs, the importance of prospective studies involving LD-CTD patients cannot be overstated. In addition, the relevance of subgrouping patients with ILD into idiopathic, definite-CTD, and LD-CTD groups should be evaluated more comprehensively, specifically regarding prognosis and treatment response. Otherwise, this classification will lack translational use in real-life situations.
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-
*
Study carried out at the Instituto do Coração - InCor, Heart Institute - University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil.
-
Financial support: None
Publication Dates
-
Publication in this collection
Mar-Apr 2015
History
-
Received
29 Sept 2014 -
Accepted
27 Feb 2014