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 Table of Contents  
Year : 2021  |  Volume : 16  |  Issue : 5  |  Page : 39-46

Interstitial pneumonia with autoimmune features

1 Consultant Rheumatologist, Apollo Hospitals, B G Road and Jayanagar, Bengaluru, India
2 Consultant Rheumatologist, Manipal Hospital, Millers Road, Bengaluru, India

Date of Submission19-Jul-2021
Date of Acceptance27-Sep-2021
Date of Web Publication21-Dec-2021

Correspondence Address:
Dr. Uma Karjigi
Apollo Hospitals, Bannerghatta Road, Bengaluru, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-3698.332977

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Interstitial pneumonia (IP) or interstitial lung disease (ILD) affect lung parenchyma, and if not treated will lead to irreparable lung damage. Classification of this group of diseases based on the etiology helps in diagnosing and managing these conditions. IP with autoimmune features (IPAF) is the term used for ILD with subtle signs of autoimmune disease but where there is insufficient evidence for it to be categorised as connective tissue disease. This review aims to look at the evidence available so far with regard to the concept of IPAF. It discusses the advantages and limitations of the current criteria, the epidemiology, clinical, radiological, serological features, management aspects, and prognosis of patients who fit into this particular entity.

Keywords: Autoantibodies, connective tissue disease-interstitial lung disease, cyclophosphamide, interstitial pneumonia with autoimmune features, mycophenolate mofetil

How to cite this article:
Karjigi U, Dharmanand BG. Interstitial pneumonia with autoimmune features. Indian J Rheumatol 2021;16, Suppl S1:39-46

How to cite this URL:
Karjigi U, Dharmanand BG. Interstitial pneumonia with autoimmune features. Indian J Rheumatol [serial online] 2021 [cited 2023 Feb 2];16, Suppl S1:39-46. Available from:

  Introduction Top

Sir William Osler described interstitial lung disease (ILD) as 'cirrhosis of the lungs'. Interstitial pneumonia (IP) also termed ILD is an umbrella term used for a family of noninfectious lung diseases. It is a heterogeneous group of diffuse parenchymal lung disorders, characterized by varying degrees of inflammation and/or fibrosis of the pulmonary interstitium, ultimately resulting in irreversible parenchymal damage. ILD is a very broad term and is classified into different types [Figure 1] depending on the pattern of lung involvement on high-resolution chest computed tomography (HRCT), lung biopsy (LB), and any associated autoimmune conditions. Patients with ILD are always thoroughly evaluated to exclude any underlying primary cause for ILD before calling them as idiopathic pulmonary fibrosis (IPF). ILD is a progressive disease. If not diagnosed and treated early it can progress to end-stage lung fibrosis. Pulmonary hypertension, cor pulmonale, hypoxic respiratory failure requiring domiciliary oxygen, depression/anxiety can be other complications impairing quality of life once fibrosis sets in.
Figure 1: Classification of ILD/IP. 1RA: Rheumatoid arthritis, 2MCTD: Mixed connective tissue disease, 3SLE: Systemic lupus erythematosus, 4NSIP: Nonspecific interstitial pneumonia, 5RB-ILD: Respiratory bronchiolitis–associated interstitial lung disease, 6DIP: Desquamative interstitial pneumonia, 7COP: Cryptogenic organizing pneumonia, 8AIP: Acute interstitial pneumonia

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There is a group of patients diagnosed with ILD/IP, having positive autoantibodies, exhibiting subtle clinical features of connective tissue disease (CTD), however, they do not fulfill the criteria for the diagnosis of definite CTD. Sometimes ILD may be the first sign of an evolving CTD. It has been found that up to 25% of patients with features of systemic autoimmune disease do not fulfill the American College of Rheumatology classification criteria for CTD.[1] On the other hand, in the absence of definite CTD 10–20% of patients with idiopathic IP have systemic symptoms and serological abnormalities indicative of systemic autoimmune process.

In this review article on IPAF, we carried out a literature review looking for English text only with the following keywords: IP with autoimmune features, IPAF epidemiological studies. All relevant articles published so far since 2015 have been reviewed through google scholar, PubMed, and research gate.

Classification Criteria

Kinder et al.[2] attempted for the first time in 2007 to classify these patients by labeling the term undifferentiated CTD (UCTD-ILD) to refer to ILD patients in the gray zone. Since then experts around the globe from different specialties (Vij et al.,[3] Corte et al.,[4] and Fischer et al.[5]) have conceptualized this entity under different terms like CTD-ILD, autoimmune featured ILD and lung dominant CTD with slightly different overlapping criteria.

Keeping in mind, the Joint committee by the American Thoracic Society and European Respiratory Society (ATS/ERS) in 2015 released an official statement designating the term IP with autoimmune features (IPAF) to describe these patients.[6] It was found that 15% of patients under this category progress to definite CTD over 4 years follow-up.[7]

American thoracic society/European respiratory Society (ATS/ERS)– 2015 Classification criteria for IP with autoimmune features:

  • Mandatory criteria:

    • Presence of IP on HRCT or LB and
    • Exclusion of alternative etiologies and
    • Does not meet the criteria for a defined CTD and,

At least one feature from two of the clinical, serological, or morphological domains

  • Clinical domain

    • Mechanics hands
    • Digital ulceration
    • Inflammatory arthritis/polyarticular joint stiffness >1 hour
    • Palmar telangiectasia
    • Raynaud's phenomenon
    • Unexplained digital puffiness
    • Gottron sign

  • Serological domain:

    • ANA ≥1:320, diffuse, speckled, homogeneous patterns (or)
    • ANA nucleolar or centromere pattern (any titre)
    • Rheumatoid factor ≥2 times upper limit of normal
    • Anti-CCP
    • ENA/ANA profile: dsDNA, SS-A, SS-B, RNP, Smith, Scl-70, PM-Scl
    • Anti-transfer RNA (tRNA) synthetase (Jo-1, PL-7, PL-12; others are: EJ, OJ, KS, Zo, tRS)
    • Anti–MDA-5.

  • Morphological domain– Radiological pattern on HRCT

    • NSIP/OP/NSIP with OP overlap/LIP

  • Histopathology patterns by surgical LB

    • NSIP/OP/NSIP with OP overlap/LIP
    • Interstitial lymphoid aggregates with germinal centers
    • Diffuse lymphoplasmacytic infiltration

  • Multicompartment involvement (in addition to ILD)

    • Unexplained pleural/pericardial effusion or thickening
    • Unexplained intrinsic airways disease
    • Unexplained pulmonary vasculopathy

  • Adapted from original classification criteria by ATS/ERS.[6]

(NSIP– Nonspecific IP; UIP– Usual IP; LIP– Lymphoid IP; OP– Organizing pneumonia)

Previously, this group of patients used to get incorrectly labeled as IPF as they wouldn't fit into the criteria for CTD-ILD. It is clinically crucial to place patients in the appropriate category as management, prognosis and survival vary. The treating physician also gains the confidence to prescribe immunosuppressive drugs at the early onset of the disease where there is a potential to stabilize the fibrotic process.

  Prevalence of Interstitial Pneumonia with Autoimmune Features in India and Across the Globe Top

As per one study, the estimated incidence of ILD is 30 cases for every 100,000 population annually. Overall prevalence annually in males is 80.9/100,000 and in females is 67.2/100,000.[8]

The prevalence of IPAF was found to be 0.17% among ILD patients according to an observational study from a center in South India.[9] Across the world, it ranges from 7.3% and 34.1% of all ILD patients in different cohorts depending on the patient recruitment centres and criteria.[8],[10],[11] In the United States, it is estimated to be 0.08% and in France 0.09% among the general population.[12],[13]

The prevalence of IPAF among undifferentiated CTD or IPF patients ranges from 7.3-91%[14] and this wide variation is probably due to the heterogeneity of the population screened. Demographic characteristics show that the mean age of IPAF patients varies from 60 to 65 years with balanced gender. However, some studies reported a lesser mean age of 55 years and a predominance of white nonsmoking women.[11],[12],[13] These are different from the CTD-ILD population where there is female preponderance.

  Clinical, Radiological and Serological Patterns Seen in Interstitial Pneumonia with Autoimmune Features Top

Clinical features

Commonly encountered clinical features in the IPAF group of patients are Raynaud's phenomenon followed by inflammatory arthritis, sicca symptoms, and mechanics hands. These are very subtle features that will be revealed only if specifically looked for. In comparison with IPF, IPAF patients were younger, had better performances in pulmonary function tests, less requirement of oxygen support, and were predominantly females.[15]

Hazarika et al.[16] in a study from North India, noticed that a significant number of patients (60%) had pulmonary artery hypertension (PAH), compared to the studies by Avala et al. (46%)[17] and Ahmad et al. (22%).[11] Patients with IPAF are at risk of developing pulmonary hypertension. Reduced 6-minute walk distance indicates the presence of PAH in this group of patients.[18] In [Table 1], we have summarized the clinical features from different studies.
Table 1: Summarises clinical features from different studies

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Serological features

ANA positivity was the most common serological feature seen in most studies. The serological features in various studies are discussed in [Table 2].
Table 2: Serological features in various studies on Interstitial pneumonia with autoimmune features

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Radiological features

In patients with IPAF, there was no predominant radiological pattern seen, however, some of the studies showed NSIP, UIP, NSIP/OP overlapping features [Table 3]. HRCT showed NSIP with a combined organizing pneumonia pattern to be more common in the IPAF group than in the non-IPAF group.[22] In patients with IPAF, presence of peri-bronchovascular distribution, subpleural sparing, pleural or pericardial effusion, and esophageal dilatation are seen. Patients with CTD-ILD more commonly exhibit NSIP or NSIP/OP overlap[21] however, in IPAF you can also see UIP pattern. Hazarika et al. noticed that the patients with Raynaud's phenomenon had a predominant UIP pattern on HRCT thorax.[16] In a study by Chartrand et al., surgical LB showed 33% NSIP and 22% UIP.[12]
Table 3: Radiological features in studies on interstitial pneumonia with autoimmune features

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Management of patients with interstitial pneumonia with autoimmune features

There has been a lot of ongoing discussion on how to manage this group of patients. Do they benefit from immunosuppression and/or antifibrotics? Or do we have to decide treatment depending on their clinical domain and underlying HRCT or biopsy pattern of lung involvement? Clinicians are extrapolating treatment options available for CTD-ILD patients to the IPAF group of patients. We need case-controlled studies looking at the management of IPAF to provide an evidence base that will help clinicians in future to come up with standard guidelines for the treatment of IPAF patients. In the current situation, it is best to tailor treatment to individual patients depending on their clinical features, serology, and pattern on HRCT or features of LB. Evidence is already emerging that antifibrotics do have a role in the treatment of patients with IPAF with more honeycombing seen on HRCT. More likely than soon it will become standard practice to combine immunosuppression along with antifibrotics depending on whether there are more ground-glass opacities or honeycombing or mixed picture on HRCT. The evidence available for various immunosuppressives and antifibrotics is discussed in [Table 4].
Table 4: Immunosuppression and/or antifibrotics - What evidence says?

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Extrapolated data from CTD-ILD studies suggest that in rapidly progressing ILD in patients with IPAF refractory to MMF, clinicians should not hesitate to optimize treatment to cyclophosphamide/rituximab unless there is a contraindication. There are also ongoing studies looking at the efficacy of tocilizumab and abatacept in these groups of patients.

Evolution to definite connective tissue disease

The evolution into definite CTD is more likely during the first few years of follow-up.[10] In two prospective studies, 13.5–15% of patients developed definitive CTD.[7],[19] The combination of female gender and the fulfilling of serological domain predicted the progression to full-blown CTD. IPAF patients should be followed up for autoimmune rheumatic diseases (ARDs). IPAF may represent a window of opportunity for early diagnosis and management, and perhaps even prevention of evolution to ARDs.[30]

Prognosis in interstitial pneumonia with autoimmune features

Conventionally, IPAF group undergoes a slower decline in lung function compared to the non-IPAF cohort of patients. The non-IPAF group treated with immunosuppressive/cytotoxic drugs tends to deteriorate faster compared to those who are in the no-treatment group.[31] It has been observed in studies that IPAF with UIP pattern tend to have a slightly worse prognosis than NSIP pattern.

The estimated 5-year survival of IPAF patients is 69.5 ± 7.8% which is significantly higher than survival observed in IPF patients.[19] In the study by Ahmad et al 1-year survival was not different between IPAF and IPF groups. In the IPAF group, the UIP pattern was not associated with the worst survival. Hazarika et al[16] noticed that the patients with inflammatory arthritis seemed to have a better-controlled disease and good response to immunosuppression. Kim et al observed a slower decline of diffusion capacity for carbon monoxide (DLCO) and total lung capacity (TLC) in the IPAF group compared to the non-IPAF-IIP group, but no differences were observed in terms of forced vital capacity (FVC) decline rate.[32] Oldham et al., created a modified IPAF cohort made of individuals satisfying the clinical domain and a HRCT or surgical lung biopsy criteria within the morphological domain. Then, they compared the survival of this modified IPAF cohort with their original IPAF cohort, CTD-ILD and IPF cohort. They found that survival of this modified IPAF cohort was similar to that of CTD-ILD, slightly better than their original IPAF cohort and much better than the IPF cohort.[13]

Adverse prognostic factors in patients with IPAF:

  • UIP pattern on HRCT
  • Multicompartmental involvement[8]
  • Low FVC and DLCO at baseline[19]
  • Older age at initial presentation, UIP pattern on HRCT/LB,[33] and lower DLCO were deemed predictive of acute exacerbation (AE) of systemic autoimmune disease-ILD while PaO2/FiO2 at the onset of AE was considered as a prognostic factor of the disease[34]
  • A worse survival rate was seen in patients with honeycombing and pulmonary artery enlargement. Non-UIP IPAF had similar survival as CTD-ILD whereas UIP-IPAF is the same as IPF[35]
  • Age, smoking history, anti-RNP positivity, and OP pattern on HRCT are predictors of worsened survival[18]
  • Older age with NSIP compared to overlap with OP or OP alone has lesser life expectancy.[22]

In a systematic review and meta-analysis by Kamiya and Panlaqui,[36]

  • Age, male gender, smoking, UIP pattern (radiological/pathological), percentage of predicted FVC, and percentage of predicted diffusing capacity of the lung for carbon monoxide (DLCO) were identified as prognostic indicators for all-cause mortality of IPAF. However, in multivariate analysis, age was associated with worse all-cause mortality of IPAF.

Yoshimura et al. reported that IPAF was an independent protective factor for AE of ILD.[37] As fibrotic changes progress in the IPF group of patients, the affected lungs become more vulnerable to external stimuli such as respiratory infection and gastric aspiration, which are noted to be a trigger for AE.[38],[39] A previous study reported that FVC was higher and the extent of honeycombing was lesser for patients with AE of systemic autoimmune disease-ILD compared to those with AE of IPF. Therefore, AE may occur even in the early stage of systemic autoimmune disease-ILD whereas AE of IPF may develop more often in the advanced stage.[40] Anti-fibrotic agents, in particular, nintedanib are reported to reduce the frequency of AE of IPF[28] and this therapeutic agent is now available to treat progressive fibrosing-ILD including systemic autoimmune disease-ILD[29] which will most likely be extrapolated to treat the IPAF group of patients.

  Points to Keep in Mind Top

  • It's critical to do a myositis profile as part of evaluations in ILD. Patients with antibodies like MDA5, tend to have rapidly progressive ILD leading to parenchymal damage and respiratory failure. Its crucial to identify this group of patients as ILD may be the only clinical feature and they may not have any extra thoracic features suggestive of inflammatory myositis.
  • Often HRCT shows features of oesophageal dilatation and/or enlarged pulmonary artery. These patients should undergo an echocardiogram to exclude pulmonary hypertension. Always ask for a history of gastro-esophageal reflux disease or dysphagia. These features direct toward autoimmune-related ILD, even though the patient may not have classical features suggestive of CTD.
  • Abnormal findings on nail-fold capillaroscopy can also provide a clue to the underlying diagnosis when clinical features are not obvious.
  • It feels more suitable to include polyarthralgia/morning stiffness rather than inflammatory arthritis in the clinical domain as when the patient has inflammatory arthritis on the clinical evaluation they will be considered as having definite CTD or rheumatoid arthritis (RA). If the second feature from the serological domain happens to be a positive anti-CCP antibody or rheumatoid factor then they are labeled as RA-ILD. Similarly, anti tRNA synthetase antibody is very specific to anti synthetase syndrome so it is a matter of debate if it was the right decision to include it in the classification criteria for IPAF
  • Unexplained weight loss, low-grade fever, gastro-oesophageal reflux disease, dysphagia were also described in some patients however the taskforce decided to drop these because of lack of specificity
  • IPAF criteria did not include ANCA which may be a drawback on the criteria as sometimes ANCA especially MPO antibody positivity is associated with IP/ILD
  • In resource-constrained settings, special antibody tests like MDA 5/anti tRNA synthetase antibody may not be easily accessible. Including ANA with cytoplasmic pattern with moderate to high titer will help to replace anti tRNA synthetase to some extent in those special circumstances
  • Sicca symptoms and serositis, which are not included in IPAF criteria, were described in a significant percentage of IPAF patients in multiple studies.[12],[19],[41] Even though these sicca symptoms lack specificity after quantifying the symptoms with standard methodology, these can be considered for inclusion in the clinical domain of the IPAF criteria
  • UIP pattern on HRCT was denied a place in this criteria, however, the task force team did comment that if the patient with UIP pattern fulfills other features on morphological domain or any two features from the clinical or serological domain they can still be classified under IPAF. Limitations of the criteria for IPAF is summarised in [Table 5] according to different domain. Limitations of the criteria for IPAF with respect to the various domains are summarised in [Table 5].
Table 5: Limitations of the criteria for interstitial pneumonia with autoimmune features

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  Conclusion Top

Interstitial Pneumonia with Autoimmune Features term is still under evolution stage and will need refining of its classification criteria as and when more evidence becomes available in future. This will help in the prognostication and give more confidence to clinicians in managing this group of patients with immunosuppression at an early stage to prevent further progression of the disease. We need more case-controlled studies to look at management options of this group of patients which will help us to come up with treatment protocols in the near future.

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Conflicts of interest

There are no conflicts of interest.

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  [Figure 1]

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]


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