The Clinical Course of Interstitial Pneumonia With Autoimmune Features

Objective of the study The objective of this study is to investigate the clinical course of IPAF to clarify the prognosis of this condition and to clarify the proportion of patients who develop clear clinical features of CTD over time. Patients will be followed prospectively for a period of 3 years, or until death or lung transplant (LTx). Predictors of LTx-free survival will be studied as well.

Rationale Interstitial pneumonia with autoimmune features (IPAF) is a chronic interstitial lung disease (ILD) with some laboratoristic and/or clinical features of autoimmune disease, but without meeting criteria of connective tissue disease (CTD), and with no other causes of ILD.

It is not uncommon for the interstitial pneumonia to be the first, and possibly the sole, manifestation of an otherwise occult CTD. The current international guidelines for the diagnosis of IIP recommend excluding CTD. For this reason, many cases of ILD with autoimmune features, but not fully meeting criteria for CTD, have been identified. Patients with IPAF, with the current diagnostic criteria, actually represent a sizable proportion of patients with ILD. However, the clinical course, prognosis and treatment approach to these patients remain unclear.

Despite recent efforts to standardize the diagnosis of IPAF, subjects with IPAF represent a very heterogenous group of patients, whose prognosis and clinical course are far from being clear. While the average age of diagnosis is higher than in CTD, there is still a female predominance. An autoimmune "flavor" may not necessarily mean a real autoimmune etiology, but currently the distinction is challenging. From this perspective, a multi-disciplinary approach together with Rheumatologist is particularly important. It also remains to be clarified what proportion of IPAF patients develop clear features of CTD over time. One issue for example is represented by the fact patient with IPAF may be treated with immunosuppressive agents, which may permanently mask the development of systemic features of CTD.

A clear distinction between IPAF and idiopathic pulmonary fibrosis (IPF), one of the most common types of ILD, is at the same time challenging and essential, as treatment is radically different in the two conditions. CTD and IPAF patients can definitely present with the same morphologic (radiographic or pathologic) pattern of usual interstitial pneumonia. However, patients with IPF respond to anti-fibrotic treatment, which is expensive, while patients with ILD secondary to CTD respond to immunosuppressive treatment. From a prognostic point of view, the survival of IPF is considered one of the worst among all types of ILD.

There is tendency to treat patients with IPAF with immunosuppressive therapy, but the rational for this remains unclear, given that the natural history of IPAF is not well known. One retrospective study suggested that the short-term prognosis of IPAF is better than that of IPF. Another retrospective study however showed that survival is worse than in CTD-ILD. At the same time, the latter study showed that patients with IPAF and UIP morphologic pattern had the same, poor prognosis of IPF patients, raising concern that they were actually IPF patients to start with and that they were mislabelled as IPAF. Again, the retrospective nature of these studies makes the results more difficult to interpret.

In 2015, in an effort to standardize the diagnosis of IPAF, the European Respiratory Society (ERS) and the American thoracic Society (ATS) published a research statement that outlined the proposed diagnostic criteria for IPAF. These include:

1. Presence of an interstitial pneumonia (HRCT or SLB) and,
2. Exclusion of alternative etiologies and,
3. Does not meet criteria of defined CTD and,
4. At least one feature from at least two of these domains A. Clinical Domain B. Serologic Domain C. Morphologic Domain
5. Clinical domain:

• Distal digital fissuring (i.e. "mechanic hands")
• Distal digital tip ulceration
• Inflammatory arthritis or polyarticular morning joint stiffness ≥60 min
• Palmar telangiectasia
• Raynaud's phenomenon
• Unexplained digital edema
• Unexplained fixed rash on the digital extensor surfaces (Gottron's sign)

Symptoms or signs of peripheral joint synovitis considered as evidence for inflammatory arthritis, but joint pain alone is not included due to its lack of specificity.

Other non-specific features, such as alopecia, photosensitivity, oral ulcers, weight loss, sicca symptoms, myalgia or arthralgia, are not included.

Demographic profiles that may be more frequently encountered in CTD (such as younger age and female, sex) are not included given their lack of specificity for CTD-ILD.

Digital fissuring ("mechanic hands"), Gottron's sign usually suggestive of anti-synthetase syndrome or systemic sclerosis-myositis overlap Raynaud's phenomenon, palmar telangiectasia, distal digital tip ulceration and digital edema are usually suggestive of scleroderma.

1. Serologic domain:

• ANA ≥1:320 titre, diffuse, speckled, homogeneous patterns or
• ANA nucleolar pattern (any titre) or
• ANA centromere pattern (any titre)
• Rheumatoid factor ≥2× upper limit of normal
• Anti-CCP
• Anti-dsDNA
• Anti-Ro (SS-A)
• Anti-La (SS-B)
• Anti-ribonucleoprotein
• Anti-Smith
• Anti-topoisomerase (Scl-70)
• Anti-tRNA synthetase
• Anti-PM-Scl
• Anti-MDA-5

1. Morphologic domain

• Suggestive radiology patterns by HRCT :

1. NSIP
2. OP
3. NSIP with OP overlap
4. LIP

• Histopathology patterns or features by surgical lung biopsy:

1. NSIP
2. OP
3. NSIP with OP overlap
4. LIP
5. Interstitial lymphoid aggregates with germinal centres

• Diffuse lymphoplasmacytic infiltration (with or without lymphoid follicles)
• Multi-compartment involvement (in addition to interstitial pneumonia):

1. Unexplained pleural effusion or thickening, pericardial effusion /thickening, intrinsic airways disease (by PFT, imaging or pathology) or pulmonary vasculopathy.

The conclusion of the research statement from ERS/ATS was that "prospective studies are urgently needed to validate the proposed classification criteria and to determine the natural history and clinical implications of a classification of IPAF", which is the purpose of this study.

Hypothesis We hypothesize that LTx-free survival in IPAF is better than in IPF, and similar to that of ILD secondary to CTD. It is also possible that different phenotypes of IPAF exist, and it may be prognostically relevant to distinguish them at the time of diagnosis.

We also hypothesize that a sizable proportion of IPAF patients may develop clear clinical or serologic features of CTD during the observation period.