A contemporary joint research statement of the European Respiratory Society/American Thoracic Society (ERS/ATS) proposed criteria for interstitial pneumonia with autoimmune features (IPAF) as an opening move in a trial to uniformly describe and categorize a subset of patients with idiopathic interstitial pneumonia that exhibit evidence of autoimmunity without meeting criteria for a defined connective tissue disease. Before this consensus report, several studies have focused on the presence of a particular subset of interstitial pneumonia, apparently idiopathic, associated with one or more clinical and serological features, suggesting a possible underlying autoimmune disorder. Several definitions and terminologies have been proposed for this specific form of interstitial pneumonia.
The aforementioned joint consensus opinion was made possible via an international expert panel of thirteen pulmonologists, four rheumatologists, one thoracic radiologist, and one pulmonary pathologist. These classifications were based on a combination of features from three domains: a clinical domain consisting of extrathoracic elements, a serological domain with specific autoantibodies, and a morphological domain with imaging patterns, histopathological findings, and multi-compartment involvement.
Interstitial lung disease (ILD) comprises of a large group of idiopathic diffuse processes that affect the lung parenchyma. Connective tissue disease-associated lung disease (CTD-ILD) represents one of the most common causes of ILD. Along with idiopathic pulmonary fibrosis (IPF), they both represent the majority of ILDs. Since CTD-ILD typically follows a better clinical course compared to IPF, and hence therapies differ substantially between them, an accurate diagnosis is critical. Up to 30% of newly diagnosed ILD will be due to CTD. This underscores the importance of investigating all patients with ILD for possible underlying CTD.
It has been determined that up to 25% of patients with features of a systemic autoimmune disease do not fulfill the American College of Rheumatology (ACR) classification criteria for connective tissue disease. On the contrary, in the absence of a defined CTD, 10-20% of patients with idiopathic interstitial pneumonia have systemic symptoms and serological abnormalities suggestive of an autoimmune process. Therefore experts from different medical specialties across the globe have conceptualized this entity as an undifferentiated CTD-associated ILD, lung-dominant CTD, and autoimmune featured ILD, using different but overlapping criteria and terminology.
It is not possible to accurately approximate the incidence and prevalence rates of ILD. Numerous prospective ILD registries have been established to address this issue. One study estimated incidence to be 30 cases of ILD for every 100,000 annually. The overall prevalence is 80.9 per 100,000 in males and 67.2 per 100,000 annually diagnosed in females. The prevalence of idiopathic interstitial pneumonia with autoimmune features (IPAF) varies between 7 and 34% of all ILDs depending on the population studied and patient recruitment profile. Regarding demographic characteristics, the mean age varies from 60-65 years, with balanced gender, although some studies reported a younger mean age of 55 and predominance of white non-smoking women. These characteristics are different from those observed in CTD-ILD, where patients are predominantly younger females and from patients with IPF who tend to be predominantly older males. IPAF patients are more frequently smokers or ex-smokers, unlike patients with UCTD-ILD, likely related to a greater percentage of 30% of cases with a usual interstitial pneumonia (UIP) pattern that meets IPAF criteria.
The pathophysiology of idiopathic interstitial pneumonia with autoimmune features (IPAF) remains evasive, as no specific studies have been conducted, and it is hypothesized that pathways involved in IPF or CTD-ILD would be involved in IPAF. It is generally considered that pathophysiological studies are challenging to design in the absence of clear diagnostic boundaries, and especially in the lack of consensus regarding IPAF being an entity.
In a study by Newton et al., differences were found between patients with IPAF and those with IPF or CTD-ILD about leukocyte telomere length, MUC5B polymorphism, but not TOLLIP polymorphism. Both telomere length and MUC5B polymorphism were associated with survival. Fewer patients with IPAF and CTD-ILD had short telomere as compared to IPF. Still, short telomere length in IPAF was associated with a faster decline in lung function and lung transplantation, similar to IPF. Although it is difficult to at this stage to fully understand the significance of these observations, and it is not known whether the genetic markers may help to guide treatment indications in the future, these results point to genetic differences between IPAF, IPF, and CTD-ILD.
Typically the first manifestation of ILD is the onset of progressive breathlessness with exertion, a persistent nonproductive cough, or pulmonary symptoms associated with another disease, such as a connective tissue disease. Prior to the consensus criteria for idiopathic interstitial pneumonia with autoimmune features (IPAF), there were four different proposed terminologies in various articles used to describe non-typical ILD entities:
It wasn't until the2015 ERS/ATS consensus paper that certain criteria were advocated. The published IPAF criteria (Table 1) required:
(1) Radiological or histopathological evidence of interstitial pneumonia and,
(2) Complete clinical evaluation excluding other etiologies for interstitial pneumonia and,
(3) Incomplete features of a defined CTD,
To meet the criteria for IPAF, cases must fulfill the three a priori requirements, in addition to a minimum of one element from at least two of the following domains:
A. Clinical domain (specific clinical features)
B. Serological domain (specific circulating autoantibodies)
C. Morphologic domain (specific chest imaging features, histopathological features, or multi-compartment involvement)
According to three published cohorts, there was a significantly higher prevalence of patients meeting serological and clinical criteria. Between 47 and 63% of IPAF patients had at least one clinical sign. The most common clinical signs were the Raynaud phenomenon (28-39%), followed by the mechanic's hands (4-29%) and Gottron sign (5 to 18%).
Clinical Domain: In this domain, particular clinical features suggestive of an underlying CTD are included. While they are specific findings, their presence alone does not allow the diagnosis of a defined CTD. Among the clinical domain features, physical signs include digital fissuring at the distal phalanges (mechanic’s hands), or ulceration at these areas, inflamed joints, or multiple joint morning stiffness that lasts more than sixty minutes, Raynaud phenomenon, palmar telangiectasia, not otherwise explained finger edema, and unexplained fixed rash on the fingers extensor aspects (Gottron sign). The task force intended to include signs and symptoms particular for autoimmune etiologies but whose nonexistence does not exclude the existence of a CTD. The congregation also advocated that, preferably, the presence of clinical features should be assessed on physical exams by experienced providers and that self-reported symptoms should not be used unaided to identify clinical domain features.
Serological Domain: Included in this domain autoantibodies with solid CTD connection (Table 1) and by requiring moderately high titers for less specific autoantibodies, such as antinuclear antibodies ANA ≥ 1:320 or rheumatoid factor (RF) at two or more than two times the higher level of normal. Non-specific indicators of inflammation, such as erythrocyte sedimentation rate or C- reactive protein, were excluded. Since the antineutrophil cytoplasmic antibody (ANCA) is related to vasculitis-associated ILD more so than ILD due to CTD, it was omitted from idiopathic interstitial pneumonia with autoimmune features (IPAF) criteria.
Morphological Domain: The morphologic domain is subdivided into three underlying sub-domains: radiographic, pathologic, and multi-compartment.
At present, it is unclear whether specific management distinct from that of IPF or CT-ILD is needed. Facts regarding idiopathic interstitial pneumonia with autoimmune features (IPAF) treatment are merely limited to case series, and further research is necessary to determine the optimal treatment approach in the IPAF population. As previously acknowledged with other ILDs, pulmonary rehabilitation, long-term oxygen supplementation therapy if applicable, and treatment of gastroesophageal reflux if existing is recommended. There have been no randomized controlled trials favoring immunomodulation in IPAF, and the proposed treatment strategies are inferred from CTD-ILD studies. In one study, patients with unclassifiable ILD, especially those meeting IPAF criteria in the non-UIP pattern, intravenous pulse cyclophosphamide was suggested to stabilize lung function. In that study, it was suggested that those with fibrosing predominant pathology, might not benefit from corticosteroids and immunosuppressive drugs, as their clinical behavior is more comparable to those with IPF.
Another large retrospective study of 125 patients with CTD-ILD encompassed nineteen patients with IPAF. In that study, mycophenolate (MMF) was related to an improved FVC in all tested patients. Different big case series investigating the benefits of rituximab in intractable interstitial lung diseases incorporated nine patients with IPAF, all of whom were managed with prednisone ± MMF before rituximab application. Of the five IPAF patients with pre- and post-rituximab pulmonary function tests (PFTs), four of five had maintenance or improvement post rituximab. An ongoing randomized, controlled phase II trial of the role of pirfenidone in patients with fibrosing undifferentiated ILD, including those who match criteria for IPAF, will be the first controlled study assessing a possible therapeutic option in this subset of patients.
The INBUILD trial suggests that nintedanib decreases the rate of ILD progression, as measured by forced vital capacity (FVC) decline in patients who have a chronic fibrosing ILD and progressive phenotype, irrespective of the underlying ILD diagnosis (including IPAF). Whether the combination of immunosuppressive therapy and antifibrotic drugs may be useful in subjects with IPAF will need to be explored in the future.
Idiopathic interstitial pneumonia with autoimmune features (IPAF) is an overlap between idiopathic interstitial pneumonia and connective tissue disease-associated ILD, so the following conditions must be ruled out while making a diagnosis of IPAF.
Review of literature implies a better prognosis for patients with idiopathic interstitial pneumonia with autoimmune features (IPAF) in comparison to patients with IPF yet marginally worse than patients with CTD-ILD. One study demonstrated an expressively inferior survival in those meeting IPAF benchmarks when compared to a CTD-ILD patient and barely slightly better survival compared to an IPF cohort. In the same study, after stratifying the premeditated population based on the occurrence of UIP on HRCT or solid lung biopsy, IPAF patients without UIP had comparable survival as a CTD-ILD population. In contrast, those with UIP had an equivalent survival as an IPF cohort.
Another study showed somewhat similar results with the survival of the modified IPAF cohort identical to that of CTD-ILD (p=0.26), and significantly better than the IPF cohort (p=0.005). Collins et al., also showed that patients meeting the IPAF criteria revealed constancy in pulmonary static and dynamic function over a 1-year follow-up period. Still, parallel trends were observed in CTD-ILD and IPF cohorts during this time. With increased documentation of patients with this disease category, more information about the prognosis shall be available.
Idiopathic interstitial pneumonia with autoimmune features (IPAF) is a progressive disease. If not diagnosed or treated early it can progress to end-stage lung fibrosis. Other complications include
The diagnosis and management of idiopathic interstitial pneumonia with autoimmune features (IPAF) need a multidisciplinary approach. The following specialties can manage these patients through teamwork.
Patients with idiopathic interstitial pneumonia with autoimmune features (IPAF) should be educated about their disease.
By following these points disease progression can be halted and complications can be minimized.
The definition of idiopathic interstitial pneumonia with autoimmune features (IPAF) has already shed light on the importance of a thorough evaluation of patients with apparently idiopathic ILD and the value of the interaction between medical specialties. IPAF and other CTD-ILD are essential to differentiate from IPF as the latter has a poor prognosis. Early diagnosis is crucial and multidisciplinary management with the involvement of a pulmonologist, radiologist, pathologist, rheumatologist and, a thoracic surgeon and is useful for the approach to IPAF, especially for consistent and accurate diagnosis and optimizing patient outcomes.
|||Fischer A,Antoniou KM,Brown KK,Cadranel J,Corte TJ,du Bois RM,Lee JS,Leslie KO,Lynch DA,Matteson EL,Mosca M,Noth I,Richeldi L,Strek ME,Swigris JJ,Wells AU,West SG,Collard HR,Cottin V, An official European Respiratory Society/American Thoracic Society research statement: interstitial pneumonia with autoimmune features. The European respiratory journal. 2015 Oct; [PubMed PMID: 26160873]|
|||Kinder BW,Collard HR,Koth L,Daikh DI,Wolters PJ,Elicker B,Jones KD,King TE Jr, Idiopathic nonspecific interstitial pneumonia: lung manifestation of undifferentiated connective tissue disease? American journal of respiratory and critical care medicine. 2007 Oct 1; [PubMed PMID: 17556720]|
|||Corte TJ,Copley SJ,Desai SR,Zappala CJ,Hansell DM,Nicholson AG,Colby TV,Renzoni E,Maher TM,Wells AU, Significance of connective tissue disease features in idiopathic interstitial pneumonia. The European respiratory journal. 2012 Mar; [PubMed PMID: 21920896]|
|||Fischer A,West SG,Swigris JJ,Brown KK,du Bois RM, Connective tissue disease-associated interstitial lung disease: a call for clarification. Chest. 2010 Aug; [PubMed PMID: 20682528]|
|||Raghu G,Remy-Jardin M,Myers JL,Richeldi L,Ryerson CJ,Lederer DJ,Behr J,Cottin V,Danoff SK,Morell F,Flaherty KR,Wells A,Martinez FJ,Azuma A,Bice TJ,Bouros D,Brown KK,Collard HR,Duggal A,Galvin L,Inoue Y,Jenkins RG,Johkoh T,Kazerooni EA,Kitaichi M,Knight SL,Mansour G,Nicholson AG,Pipavath SNJ,Buendía-Roldán I,Selman M,Travis WD,Walsh S,Wilson KC, Diagnosis of Idiopathic Pulmonary Fibrosis. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline. American journal of respiratory and critical care medicine. 2018 Sep 1; [PubMed PMID: 30168753]|
|||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. Respiratory medicine. 2009 Aug; [PubMed PMID: 19304475]|
|||Kligerman SJ,Groshong S,Brown KK,Lynch DA, Nonspecific interstitial pneumonia: radiologic, clinical, and pathologic considerations. Radiographics : a review publication of the Radiological Society of North America, Inc. 2009 Jan-Feb; [PubMed PMID: 19168837]|
|||Lee CT,Oldham JM, Interstitial Pneumonia with Autoimmune Features: Overview of proposed criteria and recent cohort characterization. Clinical pulmonary medicine. 2017 Sep; [PubMed PMID: 29276366]|
|||Mosca M,Neri R,Bombardieri S, Undifferentiated connective tissue diseases (UCTD): a review of the literature and a proposal for preliminary classification criteria. Clinical and experimental rheumatology. 1999 Sep-Oct [PubMed PMID: 10544849]|
|||Raghu G,Nyberg F,Morgan G, The epidemiology of interstitial lung disease and its association with lung cancer. British journal of cancer. 2004 Aug; [PubMed PMID: 15340372]|
|||Coultas DB,Zumwalt RE,Black WC,Sobonya RE, The epidemiology of interstitial lung diseases. American journal of respiratory and critical care medicine. 1994 Oct; [PubMed PMID: 7921471]|
|||Ahmad K,Barba T,Gamondes D,Ginoux M,Khouatra C,Spagnolo P,Strek M,Thivolet-Béjui F,Traclet J,Cottin V, Interstitial pneumonia with autoimmune features: Clinical, radiologic, and histological characteristics and outcome in a series of 57 patients. Respiratory medicine. 2017 Feb [PubMed PMID: 28137497]|
|||Chartrand S,Swigris JJ,Stanchev L,Lee JS,Brown KK,Fischer A, Clinical features and natural history of interstitial pneumonia with autoimmune features: A single center experience. Respiratory medicine. 2016 Oct [PubMed PMID: 27692137]|
|||Oldham JM,Adegunsoye A,Valenzi E,Lee C,Witt L,Chen L,Husain AN,Montner S,Chung JH,Cottin V,Fischer A,Noth I,Vij R,Strek ME, Characterisation of patients with interstitial pneumonia with autoimmune features. The European respiratory journal. 2016 Jun [PubMed PMID: 27103387]|
|||Newton CA,Oldham JM,Ley B,Anand V,Adegunsoye A,Liu G,Batra K,Torrealba J,Kozlitina J,Glazer C,Strek ME,Wolters PJ,Noth I,Garcia CK, Telomere length and genetic variant associations with interstitial lung disease progression and survival. The European respiratory journal. 2019 Apr [PubMed PMID: 30635297]|
|||Fernandes L,Nasser M,Ahmad K,Cottin V, Interstitial Pneumonia With Autoimmune Features (IPAF). Frontiers in medicine. 2019; [PubMed PMID: 31681774]|
|||Sambataro G,Sambataro D,Torrisi SE,Vancheri A,Colaci M,Pavone M,Pignataro F,Del Papa N,Palmucci S,Vancheri C, Clinical, serological and radiological features of a prospective cohort of Interstitial Pneumonia with Autoimmune Features (IPAF) patients. Respiratory medicine. 2019 Apr; [PubMed PMID: 30961944]|
|||Fischer A, Interstitial Pneumonia with Autoimmune Features. Clinics in chest medicine. 2019 Sep; [PubMed PMID: 31376895]|
|||Vij R,Noth I,Strek ME, Autoimmune-featured interstitial lung disease: a distinct entity. Chest. 2011 Nov; [PubMed PMID: 21565966]|
|||Ito Y,Arita M,Kumagai S,Takei R,Noyama M,Tokioka F,Nishimura K,Koyama T,Notohara K,Ishida T, Serological and morphological prognostic factors in patients with interstitial pneumonia with autoimmune features. BMC pulmonary medicine. 2017 Aug 14; [PubMed PMID: 28807021]|
|||Jee AS,Adelstein S,Bleasel J,Keir GJ,Nguyen M,Sahhar J,Youssef P,Corte TJ, Role of Autoantibodies in the Diagnosis of Connective-Tissue Disease ILD (CTD-ILD) and Interstitial Pneumonia with Autoimmune Features (IPAF). Journal of clinical medicine. 2017 May 4; [PubMed PMID: 28471413]|
|||Adegunsoye A,Oldham JM,Valenzi E,Lee C,Witt LJ,Chen L,Montner S,Chung JH,Noth I,Vij R,Strek ME,Husain AN, Interstitial Pneumonia With Autoimmune Features: Value of Histopathology. Archives of pathology [PubMed PMID: 28467213]|
|||Cottin V,Crestani B,Cadranel J,Cordier JF,Marchand-Adam S,Prévot G,Wallaert B,Bergot E,Camus P,Dalphin JC,Dromer C,Gomez E,Israel-Biet D,Jouneau S,Kessler R,Marquette CH,Reynaud-Gaubert M,Aguilaniu B,Bonnet D,Carré P,Danel C,Faivre JB,Ferretti G,Just N,Lebargy F,Philippe B,Terrioux P,Thivolet-Béjui F,Trumbic B,Valeyre D, French practical guidelines for the diagnosis and management of idiopathic pulmonary fibrosis - 2017 update. Full-length version. Revue des maladies respiratoires. 2017 Oct; [PubMed PMID: 28939155]|
|||Wilfong EM,Lentz RJ,Guttentag A,Tolle JJ,Johnson JE,Kropski JA,Kendall PL,Blackwell TS,Crofford LJ, Interstitial Pneumonia With Autoimmune Features: An Emerging Challenge at the Intersection of Rheumatology and Pulmonology. Arthritis [PubMed PMID: 30058242]|
|||Wiertz IA,van Moorsel CHM,Vorselaars ADM,Quanjel MJR,Grutters JC, Cyclophosphamide in steroid refractory unclassifiable idiopathic interstitial pneumonia and interstitial pneumonia with autoimmune features (IPAF). The European respiratory journal. 2018 Apr; [PubMed PMID: 29496758]|
|||Fischer A,Brown KK,Du Bois RM,Frankel SK,Cosgrove GP,Fernandez-Perez ER,Huie TJ,Krishnamoorthy M,Meehan RT,Olson AL,Solomon JJ,Swigris JJ, Mycophenolate mofetil improves lung function in connective tissue disease-associated interstitial lung disease. The Journal of rheumatology. 2013 May; [PubMed PMID: 23457378]|
|||Keir GJ,Maher TM,Ming D,Abdullah R,de Lauretis A,Wickremasinghe M,Nicholson AG,Hansell DM,Wells AU,Renzoni EA, Rituximab in severe, treatment-refractory interstitial lung disease. Respirology (Carlton, Vic.). 2014 Apr; [PubMed PMID: 24286447]|
|||Maher TM,Corte TJ,Fischer A,Kreuter M,Lederer DJ,Molina-Molina M,Axmann J,Kirchgaessler KU,Cottin V, Pirfenidone in patients with unclassifiable progressive fibrosing interstitial lung disease: design of a double-blind, randomised, placebo-controlled phase II trial. BMJ open respiratory research. 2018; [PubMed PMID: 30233802]|
|||Wells AU,Flaherty KR,Brown KK,Inoue Y,Devaraj A,Richeldi L,Moua T,Crestani B,Wuyts WA,Stowasser S,Quaresma M,Goeldner RG,Schlenker-Herceg R,Kolb M, Nintedanib in patients with progressive fibrosing interstitial lung diseases-subgroup analyses by interstitial lung disease diagnosis in the INBUILD trial: a randomised, double-blind, placebo-controlled, parallel-group trial. The Lancet. Respiratory medicine. 2020 Mar 5; [PubMed PMID: 32145830]|
|||Collins BF,Spiekerman CF,Shaw MA,Ho LA,Hayes J,Spada CA,Stamato CM,Raghu G, Idiopathic Interstitial Pneumonia Associated With Autoantibodies: A Large Case Series Followed Over 1 Year. Chest. 2017 Jul; [PubMed PMID: 28300570]|