The term undifferentiated connective tissue disease (UCTD) is used to define clinical entities characterised by features suggestive of CTD which do not meet the classification criteria of the American College of Rheumatology for a specific single disease, such as systemic lupus erythematosus, systemic sclerosis, polymyositis/dermatomyositis, and Sjögren's syndrome 123456789. UCTD can evolve in these patients over time.

As only a few reports have described lung involvement during UCTD the natural history still remains unknown and unpredictable. Interstitial lung disease (ILD) with a histological pattern of non specific interstitial pneumonia (NSIP) has recently been reported to be the most frequent lung manifestation 10111213, usually responsible for progression and adverse outcome of the disease. Lung involvement as the first clinical manifestation of UCTD is rarely reported. We discuss the case and review the associated literature of UCTD.

Up to 25% of patients who show clinical and laboratory features of systemic autoimmune diseases do not fulfil the classification criteria of ACR for a specific CTD and they are considered to have a distinct clinical entity, called UCTD 1478. The definition is still under debate, although it is becoming more definite. In 1999 and 2006 Mosca et al. reviewed the literature and proposed that preliminary classification criteria for UCTD include the following: at least one clinical manifestation of CTD, positive ANA results, and a disease duration of at least three years 48.

It may be difficult to distinguish these conditions from early phases of defined diseases such as systemic lupus erythematosus, systemic sclerosis and others. The natural history of these rare entities is variable: a high percentage of patients with UCTD maintain an undifferentiated clinical course and do not evolve to a distinct CTD, whereas some patients can evolve over time 47811.

Laboratory test screening is essential to identify markers that may suggest a systemic, autoimmune disease, or specific organ involvement. In fact, about 90% of the patients with UCTD show positive ANA 15. Capillaroscopy is useful to detect abnormalities in capillary shape and blood flow, which suggest features of Raynaud's phenomenon.

The onset of UCTD is similar to most CTDs, peaking in the middle years of life. There are no specific signs or symptoms of UCTDs because these entities present manifestations common to other CTDs. The main clinical features at onset of UCTD are arthritis and arthralgia, Raynaud's phenomenon, pleuritis and pericarditis, xerostomia and xerophtalmia, leukopenia, esophageal involvement, fever and myositis 1914. Major organ involvement is unusual and the lung has been reported as a late complication, often determining a worse outcome 15.

Recently an ATS working group described idiopathic NSIP as a distinct entity that occurs mostly in middle-aged women who never smoked and who often have positive serologic tests (antinuclear antibodies or rheumatoid factor) 16.

The typical histological findings of NSIP detected in our patient who also presented the clinical phenotype (middle-aged, non-smoking woman) suggested an additional careful investigation for an accurate rheumatologic evaluation and follow-up.

Kinder et al. recently showed that the majority of patients (88%) who met the UCTD criteria had distinct radiological and pathological features of NSIP, thus emphasizing that this pattern is peculiar of the disease 10. The same group more recently highlighted the concept that patients with UCTD and lung involvement have improved pulmonary function during the follow-up, as in our case 11 compared to other unfavourable interstitial diseases as idiopathic pulmonary fibrosis.

Lung involvement usually appears as a complication in established UCTD. There is only a recent study which has demonstrated that NSIP may be the first clinical manifestation of the disease 13, as in our case. The prospective study by Romagnoli et al. demonstrated that more than 50% of patients diagnosed with NSIP showed an autoimmune disease, as UCTD, in their follow-up. In particular, UCTD was detected in 22% of NSIP patients 13.

In conclusion, we have described a case of a patient with UCTD whose first clinical manifestation was lung involvement. UCTD should be considered when NSIP is diagnosed even in cases with evident first clinical manifestations of severe respiratory dysfunction.

A multidisciplinary approach with the intervention of pneumologists, radiologists, pathologists and rheumatologists is recommended to achieve a correct diagnosis.

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

The authors declare that they have no competing interests.

BN and EB were involved in the clinical assessment of the patient and in paper writing, FL in morphological description and paper writing, FC and PS in rheumatological investigations, FB in clinical assessment, RP in radiological evaluations, FC in pathological diagnosis and paper writing.

All authors read and approved the final manuscript.