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]

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]

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.

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)

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.

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

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)

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.

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.