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 [
1,
4,
7,
8]. 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 [
4,
8].
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 [
4,
7,
8,
11].
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 [
1,
5]. 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 [
1,
9,
14]. 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.
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