COUNTERPOINT: Does Interstitial Pneumonia With Autoimmune Features Represent a Distinct Class of Patients With Idiopathic Interstitial Pneumonia? No
2019; Elsevier BV; Volume: 155; Issue: 2 Linguagem: Inglês
10.1016/j.chest.2018.08.1073
ISSN1931-3543
AutoresJustin M. Oldham, Sonye K. Danoff,
Tópico(s)Sarcoidosis and Beryllium Toxicity Research
ResumoWhat's in a name? that which we call a rose By any other name would smell as sweet.William Shakespeare, Romeo and Juliet1GoodReadsRomeo and Juliet quotes.https://www.goodreads.com/work/quotes/3349450-romeo-and-julietGoogle Scholar What is in a name? The primary goal of disease classification is to stratify patients with common characteristics to optimize risk assessment and treatment approach. In patients with interstitial lung disease (ILD), a thorough history and physical examination, serologic evaluation, pulmonary function testing, and high-resolution CT (HRCT) scanning provide an etiology in the majority of cases, with connective tissue disease–associated ILD (CTD-ILD) being among the most common.2Duchemann B. Annesi-Maesano I. Jacobe de Naurois C. et al.Prevalence and incidence of interstitial lung diseases in a multi-ethnic county of Greater Paris.Eur Respir J. 2017; 50Crossref PubMed Scopus (143) Google Scholar When an etiology cannot be established, patients are classified as having an idiopathic interstitial pneumonia (IIP). Although idiopathic pulmonary fibrosis (IPF) is known to be the most common and deadly IIP, patients with features of autoimmune disease who fail to meet established CTD criteria represent a sizeable IIP subgroup.3Assayag D. Kim E.J. Elicker B.M. et al.Survival in interstitial pneumonia with features of autoimmune disease: a comparison of proposed criteria.Respir Med. 2015; 109: 1326-1331Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar Because the natural history of IPF and CTD-ILD differ substantially, and because immunosuppressive therapy used for CTD-ILD can harm patients who have IPF,4Raghu G. Anstrom K.J. King Jr., T.E. Lasky J.A. Martinez F.J. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis.N Engl J Med. 2012; 366: 1968-1977Crossref PubMed Scopus (1171) Google Scholar correctly identifying patients with IIP due to undiagnosed CTD is critical. To address the classification of such patients, a European Respiratory Society/American Thoracic Society task force published a research statement in 2015 proposing criteria for interstitial pneumonia with autoimmune features (IPAF).5Fischer A. Antoniou K.M. Brown K.K. et al.An official European Respiratory Society/American Thoracic Society research statement: interstitial pneumonia with autoimmune features.Eur Respir J. 2015; 46: 976-987Crossref PubMed Scopus (629) Google Scholar To meet IPAF criteria, an individual with IIP must have one feature from two of three domains: clinical, serologic, and morphologic. The clinical domain comprises physical manifestations of CTD, such as Raynaud’s phenomenon. The serologic domain includes autoantibodies common to CTD, including antinuclear antibody. The morphologic domain is separated into HRCT, histologic, and multicompartment subdomains. The HRCT and histologic subdomains include patterns commonly observed in CTD, including nonspecific interstitial pneumonia (NSIP) and organizing pneumonia. The multicompartment subdomain includes extraparenchymal manifestations of CTD. The IPAF research statement sought to establish “a uniform name and set of classification criteria.”5Fischer A. Antoniou K.M. Brown K.K. et al.An official European Respiratory Society/American Thoracic Society research statement: interstitial pneumonia with autoimmune features.Eur Respir J. 2015; 46: 976-987Crossref PubMed Scopus (629) Google Scholar Admirable as these intentions were, the striking heterogeneity in IPAF cohorts assembled to date has yielded only one reasonable conclusion; that is, patients meeting IPAF criteria do not represent a distinct class of patients with IIP. Indeed, a recent systematic review of IPAF studies concluded much the same.6Sambataro G. Sambataro D. Torrisi S.E. et al.State of the art in interstitial pneumonia with autoimmune features: a systematic review on retrospective studies and suggestions for further advances.Eur Respir Rev. 2018; 27 (pii: 170139)Crossref PubMed Scopus (44) Google Scholar Three specific areas inform this conclusion: (1) the variability in ILD cohorts selected to apply IPAF criteria; (2) the inclusion of several highly specific CTD antibodies in the serologic domain; and (3) the lack of clarity in how multicompartment features should be assessed. To date, seven IPAF cohorts have been characterized, including four in the United States (Chicago, Illinois; Denver, Colorado; Seattle, Washington; and Rochester, Minnesota), two in Europe (France and Italy), and one in Japan.7Ahmad K. Barba T. Gamondes D. et al.Interstitial pneumonia with autoimmune features: clinical, radiologic, and histological characteristics and outcome in a series of 57 patients.Respir Med. 2017; 123: 56-62Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar, 8Chartrand S. Swigris J.J. Stanchev L. Lee J.S. Brown K.K. Fischer A. Clinical features and natural history of interstitial pneumonia with autoimmune features: a single center experience.Respir Med. 2016; 119: 150-154Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 9Collins B.F. Spiekerman C.F. Shaw M.A. et al.Idiopathic interstitial pneumonia associated with autoantibodies: a large case series followed over 1 year.Chest. 2017; 152: 103-112Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 10Ferri C. Manfredi A. Sebastiani M. et al.Interstitial pneumonia with autoimmune features and undifferentiated connective tissue disease: our interdisciplinary rheumatology-pneumology experience, and review of the literature.Autoimmun Rev. 2016; 15: 61-70Crossref PubMed Scopus (59) Google Scholar, 11Ito Y. Arita M. Kumagai S. et al.Serological and morphological prognostic factors in patients with interstitial pneumonia with autoimmune features.BMC Pulm Med. 2017; 17: 111Crossref PubMed Scopus (60) Google Scholar, 12Kelly B.T. Moua T. Overlap of interstitial pneumonia with autoimmune features with undifferentiated connective tissue disease and contribution of UIP to mortality.Respirology. 2018; 23: 600-605Crossref PubMed Scopus (39) Google Scholar, 13Oldham J.M. Adegunsoye A. Valenzi E. et al.Characterisation of patients with interstitial pneumonia with autoimmune features.Eur Respir J. 2016; 47: 1767-1775Crossref PubMed Scopus (182) Google Scholar Of these, two were constructed without regard to the multicompartment subdomain (Italy and Japan) and three using patients already classified as suspected autoimmune disease (Denver, Rochester, and Italy). Only the Chicago, Seattle, and French cohorts were assembled by systematic application of the IPAF criteria to patients with IIP. Even within these studies, however, the Chicago and Seattle cohorts were limited by a large amount of noncollected serologic and multicompartment data, and the French cohort was drawn from patients with a hospital discharge diagnosis code of ILD rather than from patients evaluated through an ILD clinic. This variability in ILD cohorts has left IPAF criteria describing patients in their mid-50s (Denver, Rochester, and Seattle) or mid/late-60s (Chicago, France, and Japan) and with slight female predominance (France, Chicago, and Seattle) or strong female predominance (Denver and Italy). Nowhere is this heterogeneity more stark than in the proportion of patients with usual interstitial pneumonia (UIP), which itself does not fulfill an IPAF criterion but can co-occur with other IPAF criteria. Although UIP was observed in < 15% of patients drawn from the Denver, Rochester, and Japanese cohorts, this pattern ranged from 28% to 55% when IPAF criteria were applied systematically to IIP cohorts (France and Chicago). This undoubtedly influenced outcomes modeling, which exhibited excellent survival in IPAF cohorts with low UIP prevalence (Denver and Japan) but survival only marginally better than IPF in cohorts with higher UIP prevalence (France and Chicago) (Fig 1A). Indeed, the presence of UIP was a stronger predictor of outcome than IPAF classification (Fig 1B). The second area of concern is the specificity of autoantibodies comprising the serologic domain. Although up to 30% of the general population will have a positive antinuclear antibody,14Tan E.M. Feltkamp T.E. Smolen J.S. et al.Range of antinuclear antibodies in "healthy" individuals.Arthritis Rheum. 1997; 40: 1601-1611Crossref PubMed Scopus (725) Google Scholar most patients with an anti-aminoacyl-tRNA synthetase (anti-ARS) antibody have idiopathic inflammatory myopathy.15Lega J.C. Fabien N. Reynaud Q. et al.The clinical phenotype associated with myositis-specific and associated autoantibodies: a meta-analysis revisiting the so-called antisynthetase syndrome.Autoimmun Rev. 2014; 13: 883-891Crossref PubMed Scopus (188) Google Scholar Furthermore, approximately 70% of individuals with anti-ARS antibody have ILD, suggesting that these antibodies have higher specificity for CTD, and ILD in particular, than other antibodies comprising the serologic domain. A clinical phenotype that variably includes features of anti-ARS antibody, ILD, idiopathic inflammatory myopathy, fevers, Raynaud’s phenomenon, mechanic’s hands, and inflammatory arthritis is so well recognized that such patients are characterized worldwide as having an antisynthetase syndrome.15Lega J.C. Fabien N. Reynaud Q. et al.The clinical phenotype associated with myositis-specific and associated autoantibodies: a meta-analysis revisiting the so-called antisynthetase syndrome.Autoimmun Rev. 2014; 13: 883-891Crossref PubMed Scopus (188) Google Scholar, 16Connors G.R. Christopher-Stine L. Oddis C.V. Danoff S.K. Interstitial lung disease associated with the idiopathic inflammatory myopathies: what progress has been made in the past 35 years?.Chest. 2010; 138: 1464-1474Abstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar Features of inflammatory ILD, including NSIP and organizing pneumonia, are observed in a large majority of cases of antisynthetase syndrome,17Debray M.P. Borie R. Revel M.P. et al.Interstitial lung disease in anti-synthetase syndrome: initial and follow-up CT findings.Eur J Radiol. 2015; 84: 516-523Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar and the treatment accordingly involves suppression of the immune system, similar to that of most other CTD-ILDs. Mycophenolate mofetil and azathioprine been associated with ILD stability across CTD-ILD subtypes,18Oldham J.M. Lee C. Valenzi E. et al.Azathioprine response in patients with fibrotic connective tissue disease-associated interstitial lung disease.Respir Med. 2016; 121: 117-122Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar including those with antisynthetase syndrome.19Pinal-Fernandez I. Casal-Dominguez M. Huapaya J.A. et al.A longitudinal cohort study of the anti-synthetase syndrome: increased severity of interstitial lung disease in black patients and patients with anti-PL7 and anti-PL12 autoantibodies.Rheumatology (Oxford). 2017; 56: 999-1007Crossref PubMed Scopus (122) Google Scholar Because overt immune-mediated inflammation is a hallmark of antisynthetase syndrome, and the treatment of antisynthetase syndrome is strikingly similar to that of most CTD-ILDs, anti-ARS antibodies do not belong among criteria created to identify patients with occult CTD. Classifying patients with a positive anti-ARS antibody as IPAF may lead to missed opportunities to intervene in this inflammatory CTD early in the disease course. Others, including several authors of the IPAF research statement, have also drawn attention to this issue.20Strek M.E. Oldham J.M. Adegunsoye A. Vij R. A call for uniformity in implementing the IPAF (interstitial pneumonia with autoimmune features) criteria.Eur Respir J. 2016; 48: 1813-1814Crossref PubMed Scopus (6) Google Scholar, 21Jee A.S. Bleasel J.F. Adelstein S. Keir G.J. Corte T.J. A call for uniformity in implementing the IPAF (interstitial pneumonia with autoimmune features) criteria.Eur Respir J. 2016; 48: 1811-1813Crossref PubMed Scopus (14) Google Scholar The final area of concern is the multicompartment subdomain within the morphologic domain. At present, one of four unexplained extraparenchymal findings can satisfy this domain: pleural effusion or thickening, pericardial effusion or thickening, intrinsic airways disease, or pulmonary vasculopathy. Although these features can certainly occur in CTD, what constitutes “unexplained” and what degree of involvement is required to fulfill a particular criterion remain undefined. For example, it is difficult to say that any degree of intrinsic airways disease is “unexplained” in a former smoker. Similarly, there exists no clear point at which the presence of pulmonary hypertension becomes “unexplained,” as ILD alone can cause pulmonary hypertension that has no relation to an underlying CTD. Because many patients with ILD do not undergo screening echocardiogram or confirmatory right heart catheterization, systematic application of this criterion is unrealistic. The implication of subjectively applied multicompartment features was displayed in the Chicago IPAF cohort, in which 88% of patients with IPF who met IPAF criteria did so through the serologic and morphologic domains (Table 1), many of which through the nebulous multicompartment subdomain.13Oldham J.M. Adegunsoye A. Valenzi E. et al.Characterisation of patients with interstitial pneumonia with autoimmune features.Eur Respir J. 2016; 47: 1767-1775Crossref PubMed Scopus (182) Google Scholar It is difficult to argue that an 80-year-old male patient with UIP, 1:320 titer antinuclear antibody, and echocardiogram showing evidence of pulmonary hypertension “unexplained” by the degree of fibrosis should receive a similar classification as a 50-year-old female patient with Raynaud’s phenomenon, an anti-PM-Scl antibody, and NSIP according to HRCT imaging.Table 1IPAF Domains Met By Initial Diagnosis(Reproduced with permission from the ©ERS 2018. European Respiratory Journal Jun 2016;47(6):1767-1775; https://doi.org.10.1183/13993003.01565-2015.13Oldham J.M. Adegunsoye A. Valenzi E. et al.Characterisation of patients with interstitial pneumonia with autoimmune features.Eur Respir J. 2016; 47: 1767-1775Crossref PubMed Scopus (182) Google Scholar)Domains MetIPAF CohortInitial DiagnosisNSIP/COPIPFUCTD-ILDUnclassifiableSubjects1449497214Clinical and serologic21 (14.6)03 (6.1)17 (23.6)1 (7.1)Clinical and morphologic12 (8.3)2 (22.2)06 (8.3)4 (28.6)Serologic and morphologic73 (50.7)7 (77.8)43 (87.8)16 (22.2)7 (50)All 3 domains38 (26.4)03 (6.1)33 (45.8)2 (14.3)Data are presented as No. or No. (%). COP = crytogenic organizing pneumonia; ILD = interstitial lung disease; IPAF = interstitial pneumonia with autoimmune features; IPF = idiopathic pulmonary fibrosis; NSIP = nonspecific interstitial pneumonia; UCTD = undifferentiated connective tissue disease. Open table in a new tab Data are presented as No. or No. (%). COP = crytogenic organizing pneumonia; ILD = interstitial lung disease; IPAF = interstitial pneumonia with autoimmune features; IPF = idiopathic pulmonary fibrosis; NSIP = nonspecific interstitial pneumonia; UCTD = undifferentiated connective tissue disease. The IPAF criteria represent a first step in characterizing patients with ILD who may have CTD but do not satisfy current diagnostic criteria. Fundamental to these criteria, however, is the concept that current CTD diagnostic criteria, which often omit lung involvement as a cardinal feature, represent eternal truth. In reality, the limitations inherent to these criteria exclude some patients with clear evidence of CTD, labeling them as unclassifiable, and prompting yet another arbitrary classification scheme called IPAF. An overarching goal for our community, in conjunction with rheumatologists, should be to revise dated CTD criteria to include pulmonary involvement, which might obviate the need for IPAF altogether. Until then, we hope that IPAF authors can address the aforementioned concerns, thereby improving these criteria and leading to more homogenized IPAF cohorts. Without revision of this research statement, patients meeting IPAF criteria are far from the distinct class of patients with IIP that the IPAF authors sought to create. /cms/asset/759cfc96-681a-4d9d-8cef-016b451d8131/mmc1.mp3Loading ... Download .mp3 (29.3 MB) Help with .mp3 files Audio POINT: Does Interstitial Pneumonia With Autoimmune Features Represent a Distinct Class of Patients With Idiopathic Interstitial Pneumonia? YesCHESTVol. 155Issue 2PreviewInterstitial pneumonia with autoimmune features (IPAF) defines a distinct subset of patients with an idiopathic interstitial pneumonia (IIP). The following case from our clinic supports our position and should resonate among those who routinely evaluate patients with an interstitial lung disease (ILD). Full-Text PDF Rebuttal From Drs Oldham and DanoffCHESTVol. 155Issue 2PreviewWe agree with Drs Lee and Fischer that patients like the one described in their vignette1 have sufficient features to warrant a provisional diagnosis of unclassified connective tissue disease (CTD)-interstitial lung disease (ILD), an entity now widely referred to as interstitial pneumonia with autoimmune features (IPAF). In that respect, the IPAF research statement2 has accomplished one of its primary goals, which was to provide a single nomenclature for such patients. Unfortunately, these criteria have resulted in the lumping of patients with likely unrelated disorders into a single group. Full-Text PDF Rebuttal From Drs Lee and FischerCHESTVol. 155Issue 2PreviewWe appreciate the constructive feedback from Drs Oldham and Danoff1 with respect to ways to refine the existing classification criteria of interstitial pneumonia with autoimmune features (IPAF). However, the charge of this pro-con debate was not whether the criteria were reflective of a distinct entity, rather that the diagnosis and concept of IPAF represented a distinct entity.2 Full-Text PDF
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