Continuing Education Activity

This article is aimed at introducing idiopathic interstitial pneumonia with autoimmune features (IPAF) as a separate entity under the umbrella of interstitial lung diseases (ILD). IPAF and other connective tissue disease-associated interstitial lung disease (CTD-ILD) are essential to differentiate from IPF as the latter has a poor prognosis. Early diagnosis is essential and multidisciplinary management with the involvement of a pulmonologist, radiologist, pathologist, rheumatologist, and a thoracic surgeon is useful for consistent and accurate diagnosis and optimizing patient outcomes. This activity reviews the evaluation and management of IPAF and highlights the role of the interprofessional team in evaluating and improving care for patients with this condition.

Objectives:

• Outline the definition of interstitial pneumonia with autoimmune features (IPAF).
• Review the criteria for the diagnosis of interstitial pneumonia with autoimmune features (IPAF).
• Explain the importance of interdisciplinary team communication for the diagnosis of interstitial pneumonia with autoimmune features (IPAF).
• Summarize the potential treatment for interstitial pneumonia with autoimmune features (IPAF).

Introduction

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.[1] 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.[2][3][4] 

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.[5] 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.

Etiology

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.[5] 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.[6][7][8] This underscores the importance of investigating all patients with ILD for possible underlying CTD.[5][8]

Epidemiology

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.[9] 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.[2][4][2]

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.[10] 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.[11] 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.[12][13][14] 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.[4][14]

Pathophysiology

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.[15] 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.[15] 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.

History and Physical

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:

1) Undifferentiated CTD-ILD[2][11]

2) Undifferentiated connective tissue disease—strict definition[11][3]

3) Lung dominant-connective tissue disease[4][11]

4) Autoimmune-featured interstitial lung disease (AIF-ILD)[11][16]

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:[1]

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%).[17]

Evaluation

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).[1][18] 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.[1][8][18]

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.[8][18][19][20] Non-specific indicators of inflammation, such as erythrocyte sedimentation rate or C- reactive protein, were excluded.[19] 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.[8]

Morphological Domain: The morphologic domain is subdivided into three underlying sub-domains: radiographic, pathologic, and multi-compartment.[8]

• The radiographic subdomain describes patterns from high-resolution chest tomography (HRCT) that include non-specific interstitial pneumonia (NSIP), organizing pneumonia (OP), and lymphocytic interstitial pneumonia (LIP).[8][19][21] NSIP is the most detected pattern on HRCT in patients with CTD-ILD, and the presence of NSIP, OP, or LIP patterns on HRCT poses additional consideration of an underlying autoimmune process. Although the UIP pattern on HRCT is the most common in rheumatoid arthritis-associated ILD and is also encountered in other CTD-ILD, it was not given the equivalent influence as the other idiopathic interstitial pneumonia (IIP) patterns as it is less specific for CTD.[1][8]
• Pathological subdomain: Patients classified as IPAF had tissue specimens demonstrating non-specific interstitial pneumonia, organizing pneumonia, interstitial lymphoid aggregates, or diffuse lymphoplasmacytic infiltrate.[8][17][8] Again, although the UIP pattern can be seen in the setting of CTD, particularly rheumatoid arthritis, it is not advocated in IPAF criteria given diminished specificity.[5]
• Since CTD often has intrathoracic extra-parenchymal findings, this showed a need to add a multi-compartment subdomain. Such manifestations incorporate inexplicable pericardial or pleural effusion or thickening, pulmonary vasculopathy, and intrinsic airways disease.[8][11]

Treatment / Management

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.[22] There have been no randomized controlled trials favoring immunomodulation in IPAF, and the proposed treatment strategies are inferred from CTD-ILD studies.[11][23] 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.[24] 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.[23][25] 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.[23][26] 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.[27]

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).[28] Whether the combination of immunosuppressive therapy and antifibrotic drugs may be useful in subjects with IPAF will need to be explored in the future.

Differential Diagnosis

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.

• Idiopathic pulmonary fibrosis (IPF)
• Connective tissue disease-associated ILD (CTD-ILD)
• Cryptogenic organizing pneumonia (COP)
• Idiopathic non-specific interstitial pneumonia (NSIP)
• Lymphocytic interstitial pneumonia (LIP)

Prognosis

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.[8] 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).[29] 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.[30] With increased documentation of patients with this disease category, more information about the prognosis shall be available.

Complications

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

• Progressive lung fibrosis
• Pulmonary hypertension
• Cor pulmonale
• Hypoxemic respiratory failure requiring domiciliary oxygen
• Depression/anxiety

Consultations

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.

• Radiologist
• Pulmonologist
• Pathologist
• Rheumatologist
• Thoracic surgery (i.e. for solid lung biopsy)

Deterrence and Patient Education

Patients with idiopathic interstitial pneumonia with autoimmune features (IPAF) should be educated about their disease.

• Maintain a healthy weight
• Smoking cessation
• Avoid any environmental or occupational exposure that exacerbates lung disease
• Immunizations especially pneumococcal and annual influenza vaccination
• Pulmonary rehabilitation

By following these points disease progression can be halted and complications can be minimized.

Enhancing Healthcare Team Outcomes

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.