Interstitial pneumonia with autoimmune features (IPAF) is a disease group in which there is a combination of idiopathic interstitial pneumonia (IIP) and an underlying not further classified systemic connective tissue disease (reference: Fisher A, 2015). The condition is an example that collaboration between lung physicians and rheumatologists is useful in investigating and diagnosing.
In 2015, the European Respiratory Society/American Thoracic Society decided that interstitial pneumonia with autoimmune features (IPAF) should describe interstitial lung disease ILD combined with unspecified autoimmune disease. This means that such an underlying disease is not clearly defined. Thus, the results in blood tests, diagnostic imaging and/or tissue samples do not clearly fit into a specific connective tissue disease, even if some characteristics are present (reference: Fischer A, 2015).
Signs of lung disease range from slightly increased difficulty breathing and / or dry cough due to heavy physical exertion to severe lung failure. Rheumatic symptoms can be joint- or muscle aches, Raynaud's phenomenon, rash, fever or symptoms of various organs.
Medical history includes topical symptoms (see above) from lungs and from joints, muscles, skin and other organs.
Clinical examination maps any changes in the hands such as cracks and flaky skin on the fingers in the form of fissures and “mechanic hands” (Antisynthetase syndrome), wounds / necrosis (Systemic sclerosis), arthritis (arthritis), Raynaud's phenomenon (systemic sclerosis, MCTD), blood vessel drawings (teleangiectasias in systemic sclerosis, limited form), swollen / puffy fingers (MCTD, systemic sclerosis) and red-violet color changes (livide) skin changes over the base and middle joints of the fingers (respectively MCP and PIP joints) (Gottron's signs in Dermatomyositis).
Laboratory tests may include cell counts (red and white blood cells, platelets), liver, kidney and thyroid (metabolism) function tests, CRP, SR and creatine kinase (CK), as well as urine stings (proteins or blood). Antibody tests include ANA which is tested for ENA and subgroups by positive testing. Myositis-specific Antibodies and / or systemic sclerosis-blot should also be considered. In arthritis, rheumatic factors (RF) and anti-CCP antibody are examined. In case of suspicion Vasculitis in small or medium-sized vessels is supplemented with ANCA (PR3 and MPO) (reference: Jee AS, 2017).
Lung function tests via pulmonary physician will indicate impaired lung function which should be further investigated with imaging (see below).
Imaging is important. CT of the lungs often in the form of high-resolution chest tomography (HRCT) will most often show signs of non-specific interstitial pneumonia (NSIP), organized pneumonia (OP) or lymphocytic interstitial pneumonia (LIP) (reference: Sambataro G, 2019). Pleural and pericardial fluid may also be part of the condition.
The diagnosis is made on the basis of medical history, clinical examination, laboratory tests and diagnostic imaging.
It is generally agreed that the following three points should be met:
- Idiopatic Interstital Pneumonia (IIP) should be diagnosed on the basis of
- HRCT examinations of lungs and / or NSIP (non-specific interstitial pneumonia) -like image is most common, but UIP ("usual interstitial pneumonia") is also not uncommon in the course of the disease.
- Tissue sample (biopsy) from lung tissue
- Systemic, non-classifiable connective tissue disease is diagnosed on the basis of at least two of three (A-C) and item 3. below:
- Other causes of disease must be ruled out by thorough clinical assessment
In research, classification criteria are used. These can also be used with caution when diagnosing in clinical practice when the diagnosis is suspected in advance (see below):
Proposed classification criteria for IPAF (Fisher A, 2015).
To meet the criteria for IPAF is required:
- Radiological or histopathological evidence of interstitial pneumonia og
- Complete clinical assessment that excludes other causes of interstitial pneumonia og
- Incomplete signs of typical systemic connective tissue disease (exclude safe SLE, Sjögren's syndrome, (dermato-) Myositis, Systemic sclerosis, MCTD)
In addition to all three points above required at least one point from at least two of the three domains in columns A, B and C in the table below:
|A. Clinical features||B. Serology||C. Morphological manifestations|
|1. Distal digital fissures (mechanic hands) 2. Distal digital ulcerations on finger pulp3. Inflammatory arthritis or polyarticular joint stiffness in the morning> 60 minutes4. Palmar telangiektasi5. Raynaud's phenomenon6. Unexplained digital edema / puffy hands7. Unexplained persistent rash over the finger DIP joints (Gottron's sign)||1. ANA ≥1: 320 titer, diffuse, speckled, homogeneous pattern or|
a) ANA nuclear pattern (regardless of titer) or
b) ANA centromere pattern (regardless of titer)
Rheumatoid factor ≥2 × upper level of the reference range
5. Anti-Ro (SS-A)
6. Anti-La (SS-B)
7. Anti-ribonucleoprotein (RNP)
8. Anti-Smith (Sm)
9. Anti-topoisomerase (Scl-70)
10. Anti-tRNA synthetase (Jo-1, PL-7, PL-12, EJ, OJ, KS, Zo, tRS)
|Typical radiological pattern in HRCT|
c) NSIP with OP overlap
2. Histopathological pattern or findings on surgical lung biopsy:
c) NSIP with OP overlap
e) Interstitial lymphoid aggregates with germinal centers
f) Diffuse lymphoplasmacytic infiltration (with or without lymphoid follicles)
Multi-compartment manifestation (in addition to interstitial pneumonia):
a) Unexplained pleural fluid or pleural thickening
b) Unexplained pericardial fluid or pericardial thickening
c) Unexplained interstitial lung disease
d) Unexplained pulmonary vasculopathy
LIP: lymphoid interstitial pneumonia NSIP: non-specific interstitial pneumonia. OP, organizing pneumonia.
Similar conditions / differential diagnoses at IPAF
Symptoms and findings of IPAF overlap with other conditions. One should distinguish IPAF from the following conditions:
- Idiopathic Pulmonary Fibrosis (IPF)
- Lung disease related to specific systemic connective tissue diseases (CTD-ILD) such as Antisynthetase syndrome, Dermatomyositis og Systemic sclerosis
- Cryptogenic organized pneumonia (COP)
- Idiopathic non-specific interstitial pneumonia (NSIP)
- Lymphocytic interstitial pneumonia (LIP) (Often in Sjögren's syndrome)
Treatment of IPAF
The lung changes at IPAF range from inflammation (rheumatic inflammation) to fibrosis with increased connective tissue. While inflammation can be treated with corticosteroids (Prednisone) and other immunosuppressive drugs, fibrosis is less susceptible. However, there are anti-fibrotic drugs that can reduce or stop the development (reference: Shehata M, 2021). Good studies are not yet available, and the treatment is thus experimental (Reference: Torrisi SE, 2019).
It is recommended to consider starting treatment if the lung changes increase and include 20% or more of the lung tissue (by HRCT). The choice of medication is based on an assessment of the individual's course of the disease and is made by experienced doctors, most often specialists in lung diseases in consultation with specialists in rheumatology. Medications that are often considered are: Corticosteroids (Solu-Medrol, Prednisone), Cyclophosphamide, Rituximab, Mycophenolate, Azathioprine, Ciclosporin A.
In severe cases, some will need a lung transplant (reference: Atienza-Matheo B, 2020).
If the lung changes are the most serious manifestation, regular follow-up by a pulmonologist is essential. HRCT surveys and pulmonary function tests, possibly supplemented with a 6-minute walking test is often used. Rheumatologists often contribute with long experience with the immunosuppressive drugs and assessment of various disease manifestations outside the lungs.
Limited data are available, but preliminary results suggest that survival at IPAF is comparable to systemic connective tissue diseases with similar pulmonary manifestations and better than in idiopathic pulmonary fibrosis (Wells AU, 2020).
- Shehata M, 2021
- Fisher A, 2015
- Collins B, 2016
- SM Koo, 2017
- Fischer A, 2013
- Grans Compendium in Rheumatology